Cytotalk

Viremia-Independent T-Cell Protection by Another Protease Inhibitor

2009-07-15T15:22:00.004-05:00

In opposition to the popular and even professional medical view that protease inhibitors protect T-cells by suppressing viremia, we previously noted the finding in a study that Ritonavir's protection of T-cells from cell death was independent of any viral suppression. In the case of protease inhibitor Indinavir, another study makes a similar observation and claims the following:

The findings indicate that IDVinterferes with cell-cycle progression in primary cells but doesnot directly affect apoptosis. It is concluded that IDV may prolongcell survival indirectly by inhibiting their entry into cell cycle.In individuals on PI therapy, PI-mediated effects could potentiallymodulate immunologic responses independently of antiviral activityagainstHIV. (Blood. 2001;98:383-389)

The study's title, The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals also points to the fact that such mechanisms of the drug would be the same for those who are seronegative.

HIV-1 VPR Protein's Protective Qualities

2009-06-24T12:31:00.007-05:00

We have noted that HIV replication increases during the immune activation of opportunistic infection. A study now reveals that HIV-1 VPR protein protects against superantigens and endotoxin assault by moderating inflammatory responses and thus suppressing cell activation and cytokine production.

Even more surprising is the finding that VPR protects T cells against depletion. Says the abstract:

The HIV-1 accessory protein Vpr exhibits many interesting features related to macrophage and T cell biology. As a viral protein or as a soluble molecule it can suppress immune cell activation and cytokine production in vitro in part by targeted inhibition of NF-kappaB. In this regard we sought to test its effects in vivo on an NF-kappaB-dependent immune pathway. We examined the activity of Vpr in a lethal toxin-mediated challenge model in mice. Intravenous delivery of Vpr was sufficient to protect mice from lethal challenge with staphylococcal endotoxin B (SEB). Furthermore, Vpr protected host CD4+ T cells from in vivo depletion likely by preventing induction of AICD of SEB-exposed cells in a post-toxin-binding fashion. Understanding the biology of Vpr's activities in this model may allow for new insight into potential mechanisms of hyperinflammatory disease and into Vpr pathobiology in the context of HIV infection.

Needless to say, this runs quite counter to the assumed role which HIV is commonly believed to play in immune suppression.

Aspirin vs AZT

2008-03-28T09:59:00.005-05:00

Layman humanitarian Howard Armistead has done much homework researching the biomedical archives, speaking at reputable AIDS conferences and has been promoting SAM (Selenium, Aspirin [ASA], Multivitamin) therapy in Africa for many years with much success, oftentimes out of his own pocket. His work is admirable. He writes:

In conclusion, comparing their peak increase in CD4 cells, ASA has been shown to increase CD4 more than twice as much as AZT and is better able to sustain this increase. At the one-year point, while the CD4 count of those on AZT monotherapy decreased 25% below baseline levels, those taking aspirin maintained an average 35% increase in CD4. This reflects the fact that aspirin possesses not only anti-retroviral activity as an NF-κB inhibitor, but it can also increase immune function, again through inhibition of NF-κB.

Virus-Kills-T-Cell Paradigm Long Abandoned by Mainstream Scientists

2008-02-12T09:21:00.000-06:00

When research bearing Dr David Ho's name indicates chronic T-cell activation and programmed cell death rather than direct viral destruction as the mechanism for T-cell depletion, then the general public must then come to terms with the fact that the paradigm has shifted. However, most public education still promotes viral destruction of T cells as the actual mechanism of cell depletion.

Outdated Progesterone Research

2008-02-11T16:05:00.000-06:00

It is lamentable that this outdated article shows up with so much frequency. The claim that elevated progesterone leads to increased CCR5 chemokine receptor expression is not borne out by more recent research evidence. The results of SIV research linking progesterone to infection susceptibility have failed to be reproduced in humans, and even if women above the age of 45 are more susceptible to infection, there is little evidence that this female age group is progesterone-dominated. Women consistently present lower HIV viremia than men because of progesterone (pdf), and there is, in fact, ample recent research on progesterone's downregulation of CCR5, as well as CXCR4, receptors.

In addition, if older findings link "progesterone therapy" with elevated CCR5 expression, it is important to consider that progesterone therapy uses artificial progestins which, despite pharmaceutical claims to the contrary, react in many ways differently from the way in which natural progesterone does.

Beyond Inhibiting Protease

2008-02-11T08:51:00.000-06:00

Physicians will often tell their patients that CD4 count increases are a beneficial consequence of successful HIV viremia suppression. There is considerable evidence, however, that CD4 count improvements are due to an HIV-unrelated effect, the suppression of programmed cell death. The cited study even notes the same effect of protease inhibitors on both the lymphocytes of HIV-positive and of HIV-negative patients.

In conclusion, protease inhibitors appear to decrease CD4+ T-cell ICE expression and apoptosis before they affect Fas-R expression in HIV-infected patients. This action was independent of HIV infection, as similar effects were seen in CD4+ T cells from normal controls. Some of the benefit of protease inhibitors may be related to modification of programmed cell death, which increases CD4+ T-cell number.

Opportunistic Infections Upregulate CCR5 Expression

2008-02-08T13:41:00.000-06:00

Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression. It is not surprising that a serious infection should lead to greater immune activation, inflammation, and thus retroviral expression.

treating OI may inhibit not only the OI-induced pathology, but also limit the viral burden.

That is, if the treament protocol precludes the use of glucocorticoids.

Progesterone Inhibits CXCR4 Expression

2008-02-08T12:15:00.000-06:00

Progesterone inhibits of CCR5 and CXCR4, chemokine receptors which in excess are associated with immune deficiency progression and chronic immune activation.

Here is another study highlighting progesterone's downregulation of CXCR4.

Antiglucocorticoid Function of Androstenetriol

2008-02-07T10:52:00.000-06:00

co-culturing with βAET significantly counteracted the immunosuppressive effects of hydrocortisone on lymphocyte proliferation and cytokine production.

Corticosteroid Usage and PCP Pneumonia Prognosis

2008-02-06T15:10:00.000-06:00

Glucocorticoids augment hippocampal neurotoxicity and AIDS dementia caused by gp120. They also team up with gp120 to induce lymphocyte apoptosis. Consequently, their usage, as prescribed by CDC guidelines, raises concern among researchers. An epidemiological study highly correlates glucocorticoid therapy with a significantly lower prognosis in the treatment of PCP pneumonia.

Among severely ill patients, mortality was 3-fold higher when corticosteroids were given according to CDC guidelines. Our findings suggest that that the utility of adjunctive corticosteroids in severe PCP needs to be revisited.

Short-term vs Long-term Proliferation with Interleukin-2

2008-02-06T11:32:00.000-06:00

There is ample research pointing at lymphocyte proliferation boosting resulting from interleukin-2 treatment in the short term. However, CD4 longetivity with interleukin-2 treatment is due to decreased proliferation in the long term.

IL-2–induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation

HAART, Immune Activation, and CD4 Redistribution

2008-02-06T11:02:00.000-06:00

A previous post discusses the initial exuberant CD4 boost during the first three months of HAART, which was followed afterward by dwindling and ever diminishing increases. Another study attributes this initial boost to mere redistribution, brought about by resolution of immune activation, of lymphocytes from the lymphoid tissues to the bloodstream.

These data provide evidence suggesting that initial increases in blood CD4+ cell counts on HAART are due to redistribution and that this redistribution is mediated by resolution of the immune activation that had sequestered T cells within lymphoid tissues.

Interleukin-2 and Blood Cholesterol

2008-02-02T15:52:00.000-06:00

A major side-effect of anti-retroviral therapy is attenuated with IL-2 treatment.

IL2 treatment lowered the levels of cholesterol and low-density
lipoproteins in the blood, a result that was unexpected. (pdf)

Polyunsaturated Oils and Immune Suppression

2008-02-02T15:27:00.000-06:00

Abnormally high concentrations of polyunsaturated fats and cortisol flow in the blood serum of AIDS patients. Together with glucocorticoids, dietary polyunsaturated fats are prescribed to suppress the immune system to prevent transplanted organ rejection. This study found no difference between the immune suppression of omega-6 and omega-3, an important consideration prior to taking those much touted fish oil supplements. They do lower triglycerides, but so do many other toxic substances.

the severity of acute rejections (Banff criteria) as well as renal function after anti-rejection treatment were similar in both groups.

Stress, Cortisol, and Disease Progression

2008-01-26T19:14:00.000-06:00

A rare study links stress and cortisol levels with disease progression.

These data demonstrate that interacting effects of elevated basal cortisol and severe life stress have an impact on parameters of immune status in HIV-infected men.

...

In conclusion, these findings suggest that severe life stress, combined with high glucocorticoid activity, can lower circulating lymphocyte populations, which may then alter the host's defense against infection.

Glucocorticoids, Neurotoxicity and Dementia

2008-01-25T21:32:00.000-06:00

A prior post discusses the teaming up of cortisol and gp120 to induce apoptosis in lymphocytes. Another study, in addition, looks at the same phenomena among hippocampal neurons and suggests the potentially dire neurological consequences of the established medical practice of prescribing corticosteroids for the treatment of opportunistic infections in people with AIDS.

One of the most serious consequences of HIV infection is the frequent cases of Pneumocystis carinii pneumonia, and the current treatment of choice for serious cases involves administration of megadoses of synthetic GCs such as those used in this study (44–48). Although the number of severe cases of Pneumocystis carinii pneumonia is declining, best estimates are that thousands of individuals are still treated annually in this megadose range (e.g., 160 mg of methylprednisolone per day for 7 days). The present findings suggest that any of these routes of exposure to elevated GC concentrations might have adverse neurological consequences; this possibility remains to be tested in a clinical setting.

The study also notes the elevated incidence of hypercortisolism in the immune depressed.

HIV Infection Requires Cellular Cholesterol Rafts

2008-01-25T21:00:00.000-06:00

Aside from cholesterol's upregulation of CCR5 and CXCR4 chemokine receptors, a study claims the virus GAG protein requires cellular cholesterol rafts for attachment to the cell.

The AIDS-causing virus, HIV, must attach to cholesterol-rich regions of a cell's membrane before it can do its destructive work, researchers at the National Institute of Allergy and Infectious Diseases (NIAID) have discovered.

Stress Hormone and Viral Protein Team Up vs. Lymphocytes

2008-01-23T23:07:00.000-06:00

HIV's glycoprotein GP120 and cortisol synergize to induce CD4 lymphocyte apoptosis.

The synergistic effect of cortisol and gp- 120 in inducing apoptosis of lymphocytes is consistent with a model proposing that stress-associated and circulating HIV-1 derived soluble products may cause progression of HIV infections.

Immune Activation and CD4 Depletion

2008-01-23T15:36:00.000-06:00

While a previous post discusses T cell exhaustion, according to this study, immune activation is closely linked to CD4 depletion while the link to viremia is indirect.

In summary, our findings support a close linkage between immune activation and CD4 cell depletion in HIV infection and only an indirect relationship of these parameters to the virus rate of replication. Although the destruction-replacement hypothesis has been forcibly advocated, a strong case can be made for alternative, immune activation-centered hypotheses. Further comparative studies of the different host/virus systems would allow a more definitive delineation of cause and effect in HIV disease progression, with implications for the choice of treatment strategies.

This is consistent with the role of immune activation in T cell depletion in non-HIV infection.

A Limitation in Recombinant IL-2 Treatment

2008-01-21T10:24:00.000-06:00

Although recombinant IL-2 treatment boosts T-cell proliferation, a study previously cited in this blog also states, "Quantitation of T cell receptor excision circles and examination of thymic scans before and after administration of IL-2 suggest that thymic output does not play a major role (7, 8)."

Another post here, on the other hand, notes the thymic restoring results from treatment with recombinant IL-3. A robust thymus plays a central role in the differentiation of lymphocytes.

This may seem like too many injections, but fortunately both cytokines, along with a few others, are robustly boosted by treatment with beta androstenetriol. We have likewise noted the IL-3 boosting properties of aspirin.

Lipodystrophy and Dyslipidemia in Rwanda

2008-01-19T08:35:00.000-06:00

A new study discusses a little discussed expected side-effect of anti-retroviral treatment in Africa.

HIV-positive Rwandese patients on a World Health Organization (WHO)-recommended antiretroviral therapy regimens had a high prevalence of body fat redistribution (lipodystrophy), according to a report published in the December 1st edition of the Journal of Acquired Immune Deficiency Syndromes.

According to the study, HIV-positive patients with lipodystrophy had increased waist-to-hip ratio (WHR) and elevated cholesterol and glucose levels which put them at an increased risk of cardiovascular disease and type-2 diabetes, respectively.

International and national efforts are underway to increase universal antiretroviral access to millions of HIV-positive patients across sub-Saharan Africa. While anti-HIV treatment has undoubtedly decreased HIV-related morbidity and deaths, it is associated with lipodystrophy.

Lipodystrophy exerts a profound socio-psychological impact on the patient and the community. The disfiguration results in not only stigmatisation and marginalisation of patients but also reduced adherence to antiretroviral treatment. The latter is a risk factor for drug resistance.

DHEA Supplementation Improves Adiponectin Profile

2008-01-18T09:59:00.000-06:00

A previous post addressed the role of adiponectin deficiency in anti-retroviral dyslipidemia and lipodystrophy. However, there is evidence that DHEA supplementation improves adiponectin profiles and dyslipidemia.

Benefits of Recombinant Interleukin-2 Treatment

2008-01-16T11:08:00.000-06:00

A study on the nature of CD4 cell increases and proliferation following IL-2 treatment suggests immune-boosting benefits:

The administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound increases (often greater than 100%) in CD4 cell number and percentage. Using in vivo labeling with 2H-glucose and BrdU, we have been able to demonstrate that, although therapy with IL-2 leads to high levels of proliferation of CD4 as well as CD8 lymphocytes, it is a remarkable preferential increase in survival of CD4 cells (with half-lives that can exceed 3 years) that is critical to the sustained expansion of these cells. This increased survival was time-dependent: the median half-life, as determined by semiempirical modeling, of labeled CD4 cells in 6 patients increased from 1.7 weeks following an early IL-2 cycle to 28.7 weeks following a later cycle, while CD8 cells showed no change in the median half-life. Examination of lymphocyte subsets demonstrated that phenotypically naive (CD27+CD45RO–) as well as central memory (CD27+CD45RO+) CD4 cells were preferentially expanded, suggesting that IL-2 can help maintain cells important for host defense against new antigens as well as for long-term memory to opportunistic pathogens.

Cortisone Counteracts Cortisol-Induced Cell Death

2008-01-15T08:48:00.000-06:00

Not all glucocorticoids are lymphotoxic. Cortisone must convert to cortisol in order for lymphotoxicity to occur and cortisone will counteract cortisol's inducing of apoptosis.

Prednisone, a synthetic oxidized-GC, also suppressed the apoptosis-inducing effect of cortisol in a dose-dependent manner.

There are drawbacks to cortisol-blocking by use of prednisone or cortisone, mainly, the ready conversion of cortisone to lymphotoxic cortisol.

Immune activation, Chemokine Receptors, and Surrogate Markers

2008-01-14T17:14:00.000-06:00

An interesting vicious cycle occurs. Infection, which depends on the expression of chemokine receptors, which in turn is enhanced by immune activation, which the current paradigm dictates is determined by the degree of infection. Chemokine receptor expression increases as disease markers progress.

CXCR4 and CCR5 expression was enhanced on CD4+ T cells and correlated with HIV viral load and T cell activation. This enhancement is possibly a consequence of continuous immune activation and may contribute to HIV disease progression.

Timeline of Immune Restoration with HAART

2008-01-12T10:35:00.000-06:00

Excerpted from the abstract of this study (registration required), we find that progress with HAART is exuberant the first four months and dwindles afterwards, and reaches a plateau after three years with many patients never attaining a CD4 count sufficient to overcome immune deficiency.

Methods: A total of 1281 HIV-infected patients initiating HAART were enrolled in the AntiPROtease (APROCO) cohort. We investigated determinants of increase in CD4 count using longitudinal mixed models in patients who maintained a plasma HIV RNA <500>

Results: A total of 870 patients had a virological response at month 4. The median follow-up time was 57 months. Mean estimated increases in CD4 count in patients with persistent virological response were 29.9 cells/µL/month before month 4, 6.4 cells/µL/month between months 4 and 36, and 0.7 cells/µL/month (not significantly different from 0) after month 36. Three factors were associated with a significantly positive CD4 count slope after month 36: male gender (+0.9), no history of antiretroviral therapy at baseline (+1.7) and baseline CD4 count <100>500 cells/µL was achieved in 83% of those with a baseline CD4 count ≥200 cells/µL and in 45% of those with a baseline CD4 count <200>

Conclusion: The increase in CD4 count reaches a plateau after 3 years of virological response. Even if patients initiating HAART with low CD4 counts still show a CD4 count increase after 3 years, it remains insufficient to overcome immune deficiency in all patients.

Androstenetriol versus Infectious Microbes

2008-01-11T16:57:00.000-06:00

This study reveals that the cytokine and lymphocyte boosting hormone, androstenetriol, protects hosts from lethal infection.

Our findings show that β androstenes and analogs protect the host from lethal infection by DNA or RNA viruses such as, herpesvirus type 2, coxsackievirus B4, influenza, and arthropod borne viruses. These androstenes also protected the host from lethal bacterial infections by Enterococcus faecalis, Pseudomonas aeruginosa, and Klebsiella pneumonia and from parasites infections, i.e. Cryptosporidium parvum, and malaria.

Exercise, cortisol, and CXCR4 Expression

2008-01-11T16:16:00.000-06:00

As in the case of a previously cited study, this study of strenuous exercisers corroborates that glucocorticoids, in this case cortisol, upregulate the expression HIV binding receptor CXCR4 in lymphocytes after intense physical stress.

Progesterone, a Glucocorticoid Blocker

2008-01-11T15:07:00.000-06:00

Previous posts discuss progesterone's downregulating of the chemokine receptors which enable HIV infection and also note the upregulation of these same receptors by glucocorticoids. There is ample research demonstrating that progesterone antagonizes and blocks glucocorticoids.

Aspirin and IL-3

2008-01-10T09:28:00.000-06:00

An early post on this weblog discussed aspirin's ability to considerably improve HIV surrogate markers. Another post noted the role of recombinant interleukin-3 in the improvement of thymus, spleen, and lymphocyte profiles. In addition, there is research indicating that aspirin boosts IL-3 production.

More on Cholesterol and Entry Antagonism

2008-01-08T15:41:00.000-06:00

On a previous post, we discussed Samaritan Pharmaceutical's HIV chemokine receptor inhibitor based on cortisol inhibition and its resulting cellular cholesterol level reduction. Another study corroborates the dependence of CCR5 and CXCR4 chemokine receptors on the presence of cholesterol if HIV is to attach to them.

HAART and Glutathione Levels

2008-01-08T15:03:00.000-06:00

Glutathione is essential for lymphocytes to survive stressors and its depletion is highly correlated with disease progression. Unfortunately, HAART places a burden on its levels. With or without treatment with HAART, glutathione levels can be boosted via dietary antioxidant consumption.

Recombinant Interleukin-3 and Lymphocytes

2008-01-08T09:51:00.000-06:00

We have discussed the role of IL-2 in enduring lymphocyte restoration. However, lymphopoietic effects of IL-3 should not be overlooked. IL-3 restores thymus, spleen, and lymphocyte profiles following glucocorticoid or radiation-induced stress.

Another previous post in this blog discusses the role of androstenetriol in potently boosting the body's endogenous IL-2 and IL-3 levels with exuberant results in immune restoration.

Progesterone, an HIV Replication Inhibitor

2008-01-07T09:33:00.000-06:00

Already we have addressed progesterone's role as an HIV entry inhibitor as it downregulates chemokine receptor expression on activated lymphocytes, granted a sufficient progesterone concentration at the time of CD4 lymphocyte activation. Another study discusses placental progesterone's inhibition of replication due to its inhibition of tumor necrosis factor, TNF.

The toll of HAART

2008-01-06T16:23:00.000-06:00

Evidently, there is room for improvement in today's treatment.

Update: Here's an excerpt.

John Holloway received a diagnosis of AIDS nearly two decades ago, when the disease was a speedy death sentence and treatment a distant dream.
Yet at 59 he is alive, thanks to a cocktail of drugs that changed the course of an epidemic. But with longevity has come a host of unexpected medical conditions, which challenge the prevailing view of AIDS as a manageable, chronic disease.
Mr. Holloway, who lives in a housing complex designed for the frail elderly, suffers from complex health problems usually associated with advanced age: chronic obstructive pulmonary disease, diabetes, kidney failure, a bleeding ulcer, severe depression, rectal cancer and the lingering effects of a broken hip.
Those illnesses, more severe than his 84-year-old father’s, are not what Mr. Holloway expected when lifesaving antiretroviral drugs became the standard of care in the mid-1990s.
The drugs gave Mr. Holloway back his future.
But at what cost?

Androstenetriol for Immune Restoration

2008-01-03T10:47:00.000-06:00

While the FDA and big pharma take decades studying the benefits of recombinant IL-2 for the treatment of immume deficiency, researchers are discovering that androstenetriol may prove to be a less toxic and more natural way of significantly boosting this lymphocyte stimulating cytokine, without resorting to the syringe, while counteracting glucocorticoid immune suppression.

Androstenetriol (AET) and Androstenediol (AED) upregulate host immunity, leading to increased resistance against infections. AET augments IL-2, IL-3, IFN gamma levels, and counteracts hydrocortisone immune suppression. AET and AED at a dose of 0.75 mg/- and 8.0 mg/25-g mouse, protected 60 and 70%, respectively, of C57/BL/6J mice irradiated with a lethal dose. These hormones also protected mice irradiated with 6 Gy and infected with a coxsackievirus B4 LD50. AET significantly increased spleen lymphocyte numbers at 7, 14, and 21 days after a 6-Gy exposure. Fluorescent activated cell-sorter analysis of irradiated mice, spleen, and bone marrow showed that AET significantly augmented the myeloid precursor markers, CD11b/Mac-1, and B220 (pan B), as well as the absolute numbers of CD4+/CD8+ cells over the 21 days of testing. Overall, the data are consistent with AET/AED inducing a more rapid recovery of all hematopoietic precursors from the small number of surviving stem cells.

Glucocorticoid Depletion of Glutathione

2008-01-03T09:54:00.000-06:00

Similarly to lymphocytes, the brain and nervous system are also directly affected by immune deficiency. Since glutathione level depletion plays a major role in disease progression, the finding that brain cell glutathione levels are depleted by glucocorticoids, and hence, by cortisol, may shed light on the degenerative process taking place in AIDS dementia.

Chronic Infection and T Cell Exhaustion

2008-01-02T10:07:00.000-06:00

Our previous post on immune exhaustion due to chronic helminthic infection addressed the similarities between the immune dysregulation that occurred in HIV infection and that of prolonged helminthic infection. The article Immune Cells Fighting Chronic Infections Become Progressively 'Exhausted,' Ineffective also talks about the same dysregulation occurring with many viral infections which are prolonged, as in the case of hepatitis B and C.

"We knew that T cells responding to chronic infections become progressively compromised in many of their functional properties," says E. John Wherry, Ph.D., an assistant professor in the Immunology Program at The Wistar Institute and lead author on the Immunity study. "Put simply, the T cells become exhausted as time passes. What we wanted to learn in our study was what the specific problems were with these cells and whether their depleted state could be reversed."

Chronic diseases as those common in Africa were not mentioned in this study, but as in the case of helminths, demand consideration.

Immune Reconstitution Inflammatory Syndrome (IRIS)

2008-01-02T09:14:00.000-06:00

Opportunistic diseases previously attributed to a deficient immune system are occurring in those whose surrogate markers are improving due to HAART. The explanation given is that a newly robust immune system can lead to hyper inflammatory responses. We will overlook the fact that such was precisely the problem while the immune system was depressed and instead look at the paper entitled Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options, which describes the syndrome in detail.

Some patients initiating ART experience unique symptoms during immune system recovery. In these patients, clinical deterioration occurs despite increased CD4+ T-lymphocyte counts and decreased plasma HIV-1 viral loads [4]. This clinical deterioration is a result of an inflammatory response or "dysregulation" of the immune system to both intact subclinical pathogens and residual antigens [5-9]. Resulting clinical manifestations of this syndrome are diverse and depend on the infectious or noninfectious agent involved. These manifestations include mycobacterial-induced lymphadenitis [5], paradoxical tuberculosis reactions [6,7,10,11], worsening of progressive multifocal leukoencephalopathy (PML) [12], recurrence of cryptococcosis and Pneumocystis jirovecii pneumonia (PCP) [8,13-16], Cytomegalovirus (CMV) retinitis [17], shingles [18], and viral hepatitis [19], as well as noninfectious phenomena [20].

A Glimpse at the HIV Disease Mindset

2007-12-31T11:16:00.000-06:00

When AIDS became "HIV disease", it seems the focus shifted from the patient to the virus. This is illustrated when the same mainstream venue dismisses a drug by Samaritan Pharmaceuticals when it is introduced as an anti-cortisol treatment for AIDS, yet embraces it when it is described as a viral entry inhibitor.

As a previous post on this blog explains, receptors that are necessary for HIV attachment are upregulated by cortisol and downregulated by progesterone. It appears the infectious disease specialists would better serve their patients after a little neuro-endocrinology 101.

HAART, Lipodystrophy, and Adiponectin Deficiency

2007-12-31T09:33:00.000-06:00

A previous post in this blog discusses the role of adiponectin in lipid regulation. The study Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients discusses the link between adiponectin deficiency and HAART and the resulting lipodystrophy and dyslipidemia.

Progesterone, an Endogenous Entry Inhibitor

2007-12-30T15:53:00.001-06:00

A previous post in this blog addressed the significantly lower viral loads in immune deficient females compared to those of males, and the role that the downregulation of CCR5 receptors by progesterone plays in this discrepancy. A fascinating study explores how progesterone thus protects CD4 cells from HIV infection.

In nonactivated PBMCs, CCR5 expression remained low and was unaffected by progesterone treatment. Addition of IL-2 following anti-CD3 activation of T cells resulted in marked up-regulation of CCR5 mRNA and protein expression, consistent with previous reports. , (53) Progesterone exerted a dose-dependent inhibitory effect on CCR5 protein expression in these activated cultures. This inhibitory effect of the hormone could be seen only when progesterone was added before cell activation and was present for the entire culture period; CCR5 expression was unaltered when progesterone was added after activation of the cells, including the time of peak CCR5 expression.

In view of the extensive discussion of the genetic determinants of the CCR5 receptor's expression, endocrinological variables affecting the expression of CCR5 should likewise merit much consideration. These should include CCR5 and CXCR4 downregulation by progesterone as well as cortisol's upregulation of CXCR4 receptors, and the implications of such endocrinological factors in the treatment of immune deficiency.

Cortisol, Cholesterol, and Entry Inhibition

2007-12-28T16:22:00.000-06:00

Samaritan Pharmaceuticals appears to be connecting the dots between AIDS treatment, endocrinology, immunology, and viral control.

Samaritan scientists observed correlations between cortisol levels in HIV-infected patients and the progression of their disease to AIDS. The scientists hypothesized that the HIV-associated dysregulation of cortisol levels may play a role in the pathophysiology of AIDS including the modulation of cell-mediated immunity. Experimental evidence suggested that cortisol and its receptors were critically involved at some level in the regulation of immune function in HIV infection. Therefore, it was reasonable to hypothesize that treatment with a cortisol-modulating agent may improve the immune function in HIV-infected patients.The modulatory effect of the lead compound, SP01A, on the stress-induced corticosteroid increase may be related to a reduction of the expression of the key cholesterol synthesis enzyme 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase mRNA and reduces stress-induced synthesis of steroids in vitro and in vivo, leading to a reduction in cholesterol synthesis. Many observations have suggested that inhibitors of cholesterol synthesis inhibit cell fusion formation induced by HIV-l and that drugs extracting cholesterol from the cellular membrane exert an anti-HIV-1 effect, in vitro. The unique function of SP01A is that cholesterol synthesis inhibitors exhibited the ability to exert their effect at the cellular level.Reports from the preclinical studies suggest that there is a modification of the cholesterol content of the host cell membrane due to SP01A's effect on cholesterol synthesis. This exerts a control over the replication process as the HIV-1 virus finds it difficult to enter and infect the cell. These observations were further supported during phase I/II clinical trials in which SP01A was administered to HIV-infected individuals who were currently on stable, approved antiretroviral therapies.

Cortisol Upregulation of HIV Receptor

2007-12-28T15:16:00.000-06:00

The chemokine receptor CXCR4 has been identified as one of the mechanisms for HIV attachment and entry into T cells. The following study, Topical Glucocorticoid Therapy Directly Induces Up-Regulation of Functional CXCR4 on Primed T Lymphocytes in the Aqueous Humor of Patients with Uveitis, notes the connection between cortisol's depletion of T cells and its upregulating of CXCR4.

Indeed, a strong inverse relationship between endogenous cortisol levels in patients with AIDS and the number of circulating CD4+ T cells has been reported previously (59); it is likely that this association reflects CXCR4 induction. The current study suggests considerable caution should be used before the use of any form of glucocorticoid therapy in HIV-infected patients.

More than Viral Replication, Immune Activation is closely linked to CD4 Depletion

2007-12-28T14:22:00.000-06:00

It's good to find actual immunologists involved in the research of immune deficiency. Excerpted from CD4 T Cell Depletion Is Linked Directly to Immune Activation in the Pathogenesis of HIV-1 and HIV-2 but Only Indirectly to the Viral Load, we find the following:

Our data are consistent with a direct causal relationship between immune activation and CD4 cell depletion in HIV disease and an only indirect relation of these parameters to the virus replication rate. Invoking the concept of proximal immune activation and virus transmission, which links efficient transmission of virus to local cell activation and proliferation in response to Ags and inflammation, we propose an integrative interpretation of the data and suggest that strongly elevated immune activation induces CD4 cell depletion and not vice versa, with potential implications for the choice of treatment strategies.

Glutathione, the other Surrogate Marker

2007-12-27T17:47:00.000-06:00

It has been noted even by HIV discoverer, Dr Luc Montagnier, that disease progression requires the depletion of glutathione, the body's main endogenous antioxidant. There is evidence that glutathione levels are highly predictive of survival, regardless of CD4 count. Says Dr Montagnier,

"In HIV infected patients, the glutathione system is depressed even at early stages. The rationale is to restore the oxidative protection system back to normal."

Increased Adrenal Secretion Decreases Catabolism and Promotes Exuberant CD4 Increment

2007-12-22T11:58:00.000-06:00

Catabolic women treated with the cortisol blocker, metyrapone, gained weight and increased their CD4 count compared to women in a placebo group, whose disease progressed. Studies such as this one demonstrate the central role that adrenal dysfunction plays in immune deficiency and the benefits of addressing such adrenal insufficiency to reverse the deterioration of the patients' surrogate markers, to halt catabolism caused by cortisol and androgen deficiency, and to restore their well-being.

http://ajpendo.physiology.org/cgi/content/full/290/5/E808

Helminths and Chronic Immune Activation

2007-12-18T12:52:00.000-06:00

A publication by scientists from the Hebrew University Hadassah Medical School, Jerusalem, Israel, discusses the similarities between the chronic and debilitating immune activation which occurs in prolonged helminthic infections and that which occurs with HIV.

Chronic immune activation is one of the hallmarks of human immunodeficiency virus (HIV) infection. It is present also, with very similar characteristics, in very large human populations infested with helminthic infections. We have tried to review the studies addressing the changes in the immune profiles and responses of hosts infected with either one of these two chronic infections. Not surprisingly, several of the immune derangements and impairments seen in HIV infection, and considered by many to be the "specific" effects of HIV, can be found in helminth-infected but HIV-noninfected individuals and can thus be accounted for by the chronic immune activation itself. A less appreciated element in chronic immune activation is the immune suppression and anergy which it may generate. Both HIV and helminth infections represent this aspect in a very wide and illustrative way. Different degrees of anergy and immune hyporesponsiveness are present in these infections and probably have far-reaching effects on the ability of the host to cope with these and other infections. Furthermore, they may have important practical implications, especially with regard to protective vaccinations against AIDS, for populations chronically infected with helminths and therefore widely anergic. The current knowledge of the mechanisms responsible for the generation of anergy by chronic immune activation is thoroughly reviewed.

Aspirin Monotherapy Significantly Improves Surrogate Markers

2007-12-18T07:39:00.000-06:00

Once again, aspirin amazes. A small study at the University of Zimbabwe finds that simple aspirin mono-therapy is a potent immune modulator for those diagnosed with HIV.

The data presented in this pilot study show that, the administration of aspirin to HIV-1 infected individuals resulted in a significant increase in T lymphocytes numbers, decreases in p24 and in TNF-α. We are persuaded that there is merit in further investigating the mechanisms through which this combination increased the CD4+ cell count and defining whether this agent has any role in the HIV management algorithms.

Serum Cortisol and Polyunsaturated Fats

2007-12-16T17:10:00.000-06:00

It certainly does not sound very healthy, and indeed, it is not, at all. This old study from the Hôpital Xavier Bichat, Paris, France, reveals increasing concentrations of unsaturated fats and cortisol in the blood of AIDS patients as their disease progresses. Polyunsaturated fats and cortisol are both highly immunosuppressive substances conducive to T cell depletion, according to another study at this same hospital.

Recombinant il-2: what gives?

2007-12-16T12:30:00.000-06:00

It has been well over a decade since the first clinical trials with recombinant interleukin-2 leads to exuberant and enduring increases in CD4 counts. Although there were toxicities with higher-dosage treatment, il-2 discoverer, Kendall Smith has published the benefits and considerably improved tolerance of low-dose il-2 treatment(pdf). Considering the fast-tracking to which anti-retroviral drugs are privy, it is quite puzzling that it has been well over a decade, and there have still been no moves toward FDA approval of interleukin-2 for AIDS treatment, and, in addition, the clinical trials drag on at a snail's pace, still testing at the less tolerable dosages to boot.

Adiponectin and Lipid Regulation

2007-12-13T19:45:00.000-06:00

Adiponectin, a hormone whose deficiency is linked to anti-retroviral treatment lipodystrophy and dyslipidemia, is critical for proper metabolic function.

Earlier studies found that obese individuals and those with type 2 diabetes have reduced adiponectin concentrations, the researchers said. The new study examined the effects of that reduced adiponectin on skeletal muscle.

The researchers first examined children whose parents had type 2 diabetes and those with no family history of the disease. Muscle taken from individuals prone to diabetes was insulin resistant and had lower than normal concentrations of mitochondrial enzymes, suggesting some dysfunction, they found. The level of adiponectin also correlated with the estimated number of mitochondria in the muscle samples.

Progesterone and Lower Female HIV Viral Load

2007-12-13T15:12:00.000-06:00

The article HIV Infection Among Incarcerated Women, mentions significantly lower median viral loads in women compared to men and explains the following (the bold is mine):

A possible mechanism for this gender-based discrepancy is a difference in the expression of the HIV virion target on T-cells (CCR5 co-receptor) in women versus men. Portales and others have demonstrated a lower membrane density of CCR5 in women, which they postulate may be caused by the inhibitory effects of progesterone on CCR5 expression.(12) Because the membrane density of CCR5 determines the in vitro infectability of a target cell by an HIV-1 R5 strain, this finding could account for the gender difference seen in HIV-1 viral loads. Thus, clinicians caring for the HIV-infected woman should probably emphasize CD4 T cell count over viral load when making decisions about initiating HIV treatment.

This, in itself, does not mean that your health store progesterone cream is a cure for immune deficiency, yet it is fascinating to think that a natural hormone could potentially play an important role in holding back this intractable disease.

Update:

Here is another reference to the findings by Portales which notes lower viral loads and ccr5 expression in women and finds progesterone the most likely factor in the discrepancy.