Several recent papers offer insights into the role of the immune response in shaping the genetic make-up of HIV. In a well-publicized, open access paper by Vincent Dahirela, Karthik Shekhara and colleagues, a complex statistical approach called random matrix theory is used to analyze published HIV sequences and look for groups of sites that evolve collectively. The method allows the researchers to uncover a region of the Gag protein they dub “sector 3” that is far more constrained in its ability to mutate than surrounding areas. Additional analyses reveal this constraint is likely due to an important role in the formation of the viral capsid. In collaboration with Bruce Walker’s group at the Ragon Institute, the researchers show that HIV-specific CD8 T cell responses in elite controllers preferentially target sector 3 of Gag, consistent with prior studies indicating that immune responses in these individuals work partly by compromising viral fitness. The findings suggest that vaccines should attempt to induce T cells against this potentially vulnerable region of HIV. The researchers also recommend using their technique to search for other “multidimensionally constrained” parts of viral proteins.
In a paper published in Blood, Tao Dong and colleagues describe the impact of CD8 T cell responses on HIV diversity in a population of Chinese individuals who were infected with genetically homogenous viruses as a result of plasma donation. Because of the similarity of the infecting viruses, the cohort offers a unique window into how individual variability in the parts of HIV targeted by CD8 T cells shapes viral evolution, by selecting variants able to escape recognition. Based on analyses of four HIV proteins—Gag, Reverse Transciptase, Integrase and Nef—the researchers find evidence that 24-56% of variable sites were subject to selection by CD8 T cell responses (over approximately 10-12 years since the time of infection). The results offer strong and unusually direct evidence for the key role of virus-specific immune responses in driving HIV diversity. In a separate paper by the same authors, involving individuals from the same cohort possessing the beneficial HLA B51 immune response gene, CD8 T cell responses targeting specific epitopes from HIV Gag and Pol proteins are investigated in detail. The researchers show that mutations in these epitopes that abrogate CD8 T cell recognition are associated with higher viral loads and lower CD4 counts, whereas individuals in whom the epitopes are unmutated had higher CD4 T cell counts and lower viral loads. The findings add to the evidence that the beneficial effect of certain HLA genes in HIV infection is mediated by CD8 T cell responses targeting vulnerable parts of the virus.
Lastly, Ingrid Schellens and colleagues compare two groups of HIV-positive individuals who seroconverted in 1985 and 2005/6, respectively, to investigate whether CD8 T cell responses are altering the make-up of circulating HIV over time. The researchers report that certain HIV epitopes have become significantly less common, and these are epitopes known to be targeted by people with HLA-B alleles associated with slower HIV disease progression (such as HLA B27, B51 and B57). The implication is that HIV is adapting at the population level to avoid the most effective CD8 T cell responses, so HLA alleles that have been shown to be “protective” against disease progression in the past may not always show this association. As a possible example, the authors note that individuals with HLA B57 who seroconverted in 1985 had significantly lower viral loads than individuals lacking this allele, but this was not the case among the 2005/6 cohort.
Proc Natl Acad Sci U S A. 2011 Jun 20. [Epub ahead of print]
Coordinate linkage of HIV evolution reveals regions of immunological vulnerability.
Dahirel V, Shekhar K, Pereyra F, Miura T, Artyomov M, Talsania S, Allen TM, Altfeld M, Carrington M, Irvine DJ, Walker BD, Chakraborty AK.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02129.
Abstract
Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.
Blood. 2011 May 11. [Epub ahead of print]
Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China.
Dong T, Zhang Y, Xu KY, Yan H, James I, Peng Y, Blais ME, Gaudieri S, Chen X, Lun W, Wu H, Qu WY, Rostron T, Li N, Mao Y, Mallal S, Xu X, McMichael A, John M, Rowland-Jones SL.
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom;
Abstract
Obstacles to developing an HIV-1 vaccine include extensive viral diversity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as anti-retroviral therapy and immune pressure, including HIV-1-specific cytotoxic T-lymphocytes (CTL) that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 diversity, making it difficult to disentangle the contribution of CTL selection without employing complex analytical approaches. We describe an HIV-1 outbreak in 231 former plasma donors in China, where a narrow-source virus that had contaminated the donation system was apparently transmitted to many individuals contemporaneously. The genetic divergence now evident in these subjects should uniquely reveal how much viral diversity at the population level is solely attributable to host factors. We found significant correlations between pair-wise divergence of viral sequences and HLA class I genotypes across epitope-length windows in HIV-1 Gag, Reverse Transciptase, Integrase and Nef, corresponding to sites of 140 HLA class I allele-associated viral polymorphisms. Of all polymorphic sites across these four proteins, 24% – 56% were sites of HLA-associated selection. These data confirm that CTL pressure has a major impact on inter-host HIV-1 viral diversity and is likely to represent a key element of viral control.
J Immunol. 2011 Jun 13. [Epub ahead of print]
Multilayered Defense in HLA-B51-Associated HIV Viral Control.
Zhang Y, Peng Y, Yan H, Xu K, Saito M, Wu H, Chen X, Ranasinghe S, Kuse N, Powell T, Zhao Y, Li W, Zhang X, Feng X, Li N, Leligdowicz A, Xu X, John M, Takiguchi M, McMichael A, Rowland-Jones S, Dong T.
Beijing You An Hospital, Capital Medical University, Beijing 100069, People's Republic of China;
Abstract
Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B' HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51-associated HIV-1 control. We focused on the T cell responses against three dominant HLA-B51-restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51(+) individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51(+) individuals. Good control of viral load and higher CD4(+) counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4(+) counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations.
AIDS. 2011 Jun 15. [Epub ahead of print]
Loss of HIV-1 derived CTL epitopes restricted by protective HLA-B alleles during the HIV-1 epidemic.
Schellens IM, Navis M, van Deutekom HW, Boeser-Nunnink B, Berkhout B, Kootstra N, Miedema F, Keşmir C, Schuitemaker H, van Baarle D, Borghans JA.
Abstract
OBJECTIVE AND DESIGN: HIV-1 is known to adapt to the human immune system, leading to accumulation of escape mutations during the course of infection within an individual. Cross-sectional studies have shown an inverse correlation between the prevalence of HLA alleles in a population and the number of CTL escape mutations in epitopes restricted by those HLA alleles. Recently, it was demonstrated that at a population level HIV-1 is adapting to the humoral immune response, which is reflected in an increase in resistance to neutralizing antibodies over time. Here we investigated whether adaptations to cellular immunity have also accumulated during the epidemic. METHODS: We compared the number of CTL epitopes in HIV-1 strains isolated from individuals who seroconverted at the beginning of the HIV-1 epidemic and from individuals who seroconverted in recent calendar time. RESULTS: The number of CTL epitopes in HIV-1 variants restricted by the most common HLA alleles in the population did not change significantly during the epidemic. In contrast, we found a significant loss of CTL epitopes restricted by HLA-B alleles associated with a low relative hazard of HIV-1 disease progression during the epidemic. Such a loss was not observed for CTL epitopes restricted by HLA-A alleles. CONCLUSIONS: Despite the large degree of HLA polymorphism, HIV-1 has accumulated adaptations to CTL responses within twenty years of the epidemic. The fact that such adaptations are driven by the HLA-B molecules that provide best protection against HIV-1 disease progression has important implications for our understanding of HIV evolution.
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