Viremia-Independent T-Cell Protection by Another Protease Inhibitor

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 IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV. (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

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

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

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

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

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

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

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

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

Corticosteroid Usage and PCP Pneumonia Prognosis

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.