Research Initiative Treatment Action (RITA!); Vol 6, No. 2 June 2000
Thomas Gegeny
Although the past decade has seen great strides in the treatment of HIV, much about the virus remains obscure. Drug development to date has mainly followed from research characterizing the life cycle of HIV (for instance, targeting viral reverse transcriptase or protease enzymes to interrupt viral replication). This approach has proven therapeutic, but not curative, against HIV. In many cases, viral mutation produces eventual resistance to these drugs and the disease marches on.
So then what are other approaches to developing effective antiretroviral therapy, besides directly studying viral life cycle? One approach is to study the variability associated with viral infection and pathogenesis: instances where the virus is not "performing optimally." For instance HIV-2, which is primarily found in West Africa, is considered less pathogenic than HIV-1 because people infected with HIV-2 maintain higher CD4 T cell counts for longer periods of time and therefore take more time to progress to AIDS. Also, the very fact that HIV propagates is almost a mystery in itself because of its high rate of mutation; HIV is constantly making mistakes during replication.
Another approach, immune-based research, has been slowly gaining interest since the idea of HIV "eradication" appears impossible with the current drugs. An adjunct to immune-based research has been the close study, since the early 1990s, of HIV-infected individuals who have not progressed to AIDS in 10 or more years and who have not taken antiretroviral therapy. Many of these long-term nonprogressors (LTNPs) have been reclassified as "slow-progressors" because they eventually began to show signs of disease progression. Yet some have not—even after more than 15 years of HIV infection. The study of delayed HIV disease progression, and in some instances nonprogression, has brought up many hypotheses about what it might take to keep HIV under control and where the virus may be vulnerable.
One premise is clear from the studies of LTNPs thus far: not all LTNPs are the same. Some LTNPs show distinct features not shared by others, yet somehow all experience delayed HIV disease progression or nonprogression. The reasons behind this phenomena may be virologic, immunologic or both. However, no common genetic correlate has yet been identified to explain long-term nonprogression.
Controlling the virus…but how? LTNPs have one distinct advantage: they are able to suppress viral replication and maintain stable CD4 T cell levels over time in the absence of antiretroviral therapy. A recent study by French investigators (J Med Virol, 1999 Jul;58(3):256-63) reconfirmed that LTNPs maintain stable viral loads, but that the levels can vary greatly between individuals. At one year of follow-up, some LTNPs maintained undetectable viral loads, while others maintained stable viral loads at levels greater than 10,000 copies/mL. The researchers noted that blood samples from LTNPs had less CD4 T cell-associated virus when compared to control samples from slow progressors. Similarities have been observed between LTNPs and individuals who have recently seroconverted. One study revealed mostly similar distributions of CD4 and CD8 T cell subsets in LTNPs and patients in the early phase of infection (Clin Diagn Lab Immunol, 1998 Sep;5(5):662-6). Similarly, strong polyclonal CD4 T cell responses specific to HIV were observed both in LTNPs and patients who received combination antiretroviral therapy during acute infection (Science, 1997 Nov 21;278(5342):1447-50). An earlier study revealed similar HIV proviral DNA (viral DNA incorporated within the host chromosome) and messenger RNA expression levels in samples of peripheral blood mononuclear cells collected from LTNPs and recent seroconverters (J Virol, 1996 Dec;70(12):9035-40). The difference between LTNPs and recent seroconverters is that for most HIV-infected persons, these cellular and molecular profiles change as disease progression ensues, while this is not necessarily the case for LTNPs.
Many other studies present wide-ranging, and at times inconclusive or contradictory, observations in LTNPs:
Clearly there is much more to learn. Indeed there is increasing consensus that for many LTNPs a combination of factors may be at work and that these additive effects may vary with the individual.
Viral genetic evidence. Many studies have looked at the genetic distinctions that might explain delayed HIV disease progression. Considerable research investigating the viral genotype of LTNPs has focused on deletions in the nef gene of HIV seen in some nonprogressors. The Nef protein is an HIV regulatory protein whose role in vivo has not yet been clearly identified. While many researchers have observed defective nef gene alleles in LTNPs, others have not. An Australian cohort of patients (one blood donor and several transfusion recipients) has been the focus of considerable study ever since nef-deleted virus was discovered in those individuals and postulated to be the reason for their lack of disease progression (Science, 1995 Nov 10;270(5238):988-91). However, subsequent studies of these individuals show variability even between these individuals (Int Conf AIDS, 1998, Abstracts no. 11140 & 13348). Only one nonprogressor in a cohort of American hemophilic LTNPs has been identified as carrying nef-deleted virus (J Infect Dis, 1999 Dec;180(6):1790-802). A study in Swedish and Italian LTNPs found even less evidence for nef gene defects, with the exception of a valine/isoleucine substitution at position 11 that was significantly correlated with a lower probability of disease progression (J Hum Virol, 1998 Jul-Aug;1(5):320-7). Recently, a study in HIV-infected LTNP intravenous drug users in Italy found few altered nef sequences, let alone gross deletions (J Med Virol, 2000 Mar;60(3):294-9). However, work by another group of Italian investigators confirmed the presence of defective nef genes in higher percentages of LTNP hemophiliacs than progressor hemophiliacs (Virology, 1999 Jul 5;259(2):349-68).
Obviously, the evidence to date is inconclusive. Research suggests that altered nef sequences may play a role in nonprogression for some LTNPs, but certainly not all. What is compelling about these findings is that such deletions are more or less irreversible. Polymorphisms that are difficult to reverse may be a key to understanding how to slow disease progression (for example, J Virol, 2000 May;74(9):4361-76). If the virus mutates in a manner counterproductive to its own pathogenicity, can science take advantage of this trait to select for weaker forms of HIV in the development of therapeutic vaccines or other treatments? To date, no one has been able to do this.
Host genetic evidence. Much attention has been placed on aspects of human genetic variability that may be responsible for reduced HIV susceptibility. A polymorphism in the CCR5 receptor gene, in particular, has prompted a great deal of research. The CCR5 molecule is an important coreceptor used by HIV to gain access inside CD4 T cells (the primary receptor is the CD4 molecule itself). Several studies have shown that a 32 base pair deletion in the gene for CCR5 may interfere with the progression of HIV. In fact, individuals who are homozygous for this mutation (having inherited two copies, one from each parent) may be resistant to infection by CCR5-tropic virus, as indicated by research in multiply exposed, but HIV-negative, individuals (Cell, 1996 Aug 9;86(3):367-77). The degree of protection conferred by this mutation has not been determined with regard to virus tropic for other receptors. Subsequent research has shown that some LTNPs are heterozygous for the CCR5 mutation, called "CCR5 delta 32," i.e. one wild-type copy of CCR5 and one copy with the 32 base pair deletion (Ann Intern Med, 1997 Nov 15;127(10):882-90; Mol Med, 1997 Jan;3(1):23-36). This may be an explanation why heterozygous individuals respond better to highly active antiretroviral therapy (7th Conference on Retroviruses and Opportunistic Infections, Abstract 452, San Francisco, 2000).
Unfortunately, as with the nef deletion scenario, the CCR5 mutation is not the only explanation for delayed progression or nonprogression of HIV disease. Two studies that compared immunologic and virologic parameters in LTNPs with wild-type CCR5 and those with a heterozygous CCR5 (containing a copy of the deletion) showed no differences between the groups, thus suggesting other immunologic or virologic factors are involved (J Clin Invest, 1997 Sep 15;100(6):1581-9; Eur J Immunol, 1997 Dec;27(12):3223-7). Several chemokine receptor molecules have also been studied including the CCR2 and the CXCR4 molecules. As with CCR5, no common genetic correlate has been identified that can explain the LTNP phenomenon.
Other research has focused on human leukocyte antigen (HLA) molecules that are part of the major histocompatibility complex of the immune system. HLA proteins attach to antigens (such as virus particles) within an infected cell and then display the antigens at the cell surface to induce the destruction of the infected cell by cytotoxic T lymphocytes. Several studies have found certain subtypes and combinations of these molecules associated with LTNPs. For example, one study observed that CD8 T cell responses specific for the HIV envelope protein were restricted by HLA-Cw7 in LTNPs (Viral Immunol, 1998;11(3):119-29). Furthermore, some encouraging findings along these lines were published in the March 14 issue of the Proceedings of the National Academy of Sciences USA (2000 Mar 14;97(6):2709-14). Researchers used HLA typing to reveal that the HLA B*5701 class I gene family was found in 11 of 13 LTNPs (85%) and in only 19 of 200 progressors (9.5%). Also in another study investigators were able to correctly classify 70% of LTNPs and 81% of progressors based on parameters that looked at CCR5, CCR2, SDF-1 (a molecule that binds to CXCR4), and HLA genotypic information (Blood, 1999 Feb 1;93(3):936-41). Perhaps science is closing in on understanding how genetics can delay HIV disease progression.
Further research with LTNPs will undoubtedly reveal more information. Such research may determine the secrets of immune-mediated control of HIV manifested through nonreversible viral mutations, host genetic composition or a combination of these factors. Just as the development of HIV entry inhibitors (see page 6 of this issue) grew from discoveries of the mechanism of viral infection in CD4 T cells, so too will other discoveries inspire novel therapeutic strategies, perhaps even a cure. The question is when?
20000610
RI000604
Copyright © 2000 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
ÆGiS is made possible through unrestricted grants from Roxane Laboratories, Inc., iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2000. This material is designed to support, not replace, the relationship that exists between you and your doctor.
ÆGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Copyright ©1985, 2000. ÆGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on ÆGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of ÆGIS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.