A new study by Paul Goepfert and colleagues offers compelling evidence that CD8 T cell responses can pressure HIV into mutating in ways that compromise viral fitness. CD8 T cells target tiny slices of viral proteins called epitopes, which are displayed by infected cells as a sort of alarm signal; CD8 T cells that recognize a particular epitope (via a docking bay-type structure called a T cell receptor or TCR) can mediate destruction of an infected cell by releasing cell-destroying substances such as perforin and granzyme B. HIV mutations that impact the structure of an epitope can abrogate CD8 T cell recognition and this phenomenon is called immune escape (it is loosely analogous to the way mutations can allow the virus to resist the effects of antiretroviral drugs). If a particular epitope-specific CD8 T cell response is effective, viruses with escape mutations in that epitope are at a selective advantage because they can persist despite the presence of the immune response. However, certain parts of HIV can tolerate mutations more easily than others, and studies have shown that the Gag protein is so vital to replication that mutations affecting epitopes in Gag can impair the ability of the virus to replicate in a lab dish (in vitro).
To assess whether these observations are relevant in people, Goepfert et al analyzed data from 114 epidemiologically linked transmission pairs in Zambia (the individuals had been participants in a larger cohort of “discordant” couples in which one partner was HIV-infected; despite counseling and increased condom use in the cohort, transmission still occurred at a rate of approximately 8% per year). The researchers looked for evidence of CD8 T cell escape mutations in Gag and Nef and then analyzed whether the transmission of HIV containing mutations impacted viral load in the newly infected individual. The timepoint for the analysis was 6 months after infection, because 579 of the 610 mutations documented in the transmitting partners were still present in recipients at this time point. The results showed that higher numbers of CD8 T cell escape mutations in the Gag protein of transmitted viruses were significantly associated with lower viral loads in the newly infected individuals (no such effect was seen for Nef). Further analyses revealed that the effect was most consistent for Gag epitopes targeted by HLA-B-restricted CD8 T cells (HLA genes manufacture the CD8 T cell TCR and thus govern the epitope structures that a CD8 T cell can recognize). The researchers hypothesized that the impact on HIV replication of mutations in epitopes targeted by HLA-B-restricted CD8 T cells would be most prominent in individuals lacking the same HLA-B genes themselves, and indeed this turned out to be the case: when the analysis was restricted to only these study participants the associations between more mutations in Gag and lower viral load became much stronger (p=0.0003).
In discussing their results, the study authors note that there was a ~10-fold difference in viral loads when individuals infected with viruses containing less than two escape mutations in Gag were compared to those with more than six such mutations, suggesting that infection with these multiple escape mutants may slow disease progression (although longer term follow up of a subset of participants indicates that viral load is, as is typical, increasing over time). They also state that: “these data imply that for CTL-based HIV vaccines to effectively control viral load, they must simultaneously target multiple Gag epitopes, thereby ensuring that fitness constraints prevent the virus from easily mutating.” In an accompanying news brief, JEM editor Hema Bashyam speculates that the study “might explain why a T cell vaccine that induces immune responses against two Gag epitopes failed in a recent trial.” In fact, recipients of the Merck HIV vaccine developed responses to an average of just one Gag epitope.
The Journal of Experimental Medicine
Published online 21 April 2008
doi:10.1084/jem.20072457
BRIEF DEFINITIVE REPORT
Paul A. Goepfert1,2, Wendy Lumm4, Paul Farmer4, Philippa Matthews5, Andrew Prendergast5, Jonathan M. Carlson6,7, Cynthia A. Derdeyn4,8, Jianming Tang1,2, Richard A. Kaslow3, Anju Bansal1, Karina Yusim10, David Heckerman6, Joseph Mulenga11, Susan Allen9, Philip J.R. Goulder5,12,13, and Eric Hunter4,8
1 Department of Medicine, 2 Department of Microbiology, and 3 Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294
4 Emory Vaccine Center at Yerkes National Primate Research Center, Atlanta, GA 30322
5 Department of Pediatrics, The Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, England, UK
6 Microsoft Research, Redmond, WA 98052
7 Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195
8 Department of Pathology and Laboratory Medicine and 9 Department of Global Health, Emory University, Atlanta, GA 30322
10 Los Alamos National Laboratory, Los Alamos, NM 87545
11 Zambia-Emory HIV Research Group, Lusaka, Zambia
12 HIV Pathogenesis Program, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa
13 Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, MA 02129
CORRESPONDENCE Paul A. Goepfert: paulg@uab.edu
In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)–associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele–restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.
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