Host HLA B*Allele-Associated Multi-Clade Gag T-Cell Recognition Correlates with Slow HIV-1 Disease Progression in Antiretroviral Therapy-Naïve Ugandans

Abstract

BackgroundSome HIV infected individuals remain asymptomatic for protracted periods of time in the absence of antiretroviral therapy (ART). Virological control, CD4 T cell loss and HIV-specific responses are some of the key interrelated determinants of HIV-1 disease progression. In this study, possible interactions between viral load, CD4 T cell slopes, host genetics and HIV-specific IFN-γ responses were evaluated in chronically HIV-1-infected adults.Methodolology/Principal FindingsMultilevel regression modeling was used to stratify clade A or D HIV-infected individuals into disease progression groups based on CD4 T cell slopes. ELISpot assays were used to quantify the frequency and magnitude of HIV-induced IFN-γ responses in 7 defined rapid progressors (RPs) and 14 defined slow progressors (SPs) at a single time point. HLA typing was performed using reference strand conformational analysis (RSCA). Although neither the breadth nor the magnitude of the proteome-wide HIV-specific IFN-γ response correlated with viral load, slow disease progression was associated with over-representation of host immunogenetic protective HLA B* alleles (10 of 14 SPs compared to 0 of 7; p = 0.004, Fisher's Exact) especially B*57 and B*5801, multiclade Gag T-cell targeting (71%, 10 of 14 SPs compared to 14%, 1 of 7 RPs); p = 0.029, Fisher's Exact test and evident virological control (3.65 compared to 5.46 log10 copies/mL in SPs and RPs respectively); p<0.001, unpaired student's t-testConclusionsThese data are consistent with others that associated protection from HIV disease with inherent host HLA B allele-mediated ability to induce broader Gag T-cell targeting coupled with apparent virological control. These immunogenetic features of Gag-specific immune response which could influence disease progression may provide useful insight in future HIV vaccine design.

For Protection from HIV-1 Infection, More Might Not Be Better: a Systematic Analysis of HIV Gag Epitopes of Two Alleles Associated with Different Outcomes of HIV-1 Infection

“…Specifically, studies have shown that CD8 ϩ T cell responses to HIV-1 Gag are associated with viremia control (25,37,49,54,58,62). Characterization of CD8 ϩ T cell responses correlated with protection from HIV-1 infection needs to be conducted with PBMCs from individuals who are highly exposed but remain uninfected (HESN).…”

“…To deal with the diver- sity of HIV-1 virus, a mosaic vaccine approach has been developed (13,17,20,31,59), and it appears to have enhanced coverage of diverse HIV strains (13,59). In addition to the reports that Gag specific T cell responses are associated with lower viral loads (25,30,37,49,54,58,62,74), studies have suggested that the failure of current vaccine approach may be due to targeting immunodominant variable epitopes and vaccine approaches targeting conserved regions of HIV-1 have been proposed and are under investigation (38,55,73). The narrowly focused antigen presentation of multiple variants by A*01:01 could be advantageous in dealing with viral diversity, in the meantime avoiding the negative effect of immunodominance of mutable epitopes (55).…”

“…The associations of specific HLA alleles with different outcomes of HIV-1 infection are most likely due to the differences in the antigenic peptides or epitopes of HIV being presented and the resulting immune responses following antigen recognition. Moreover, T cell responses to HIV-1 Gag correlate with viremia control and better outcomes of disease progression (25,30,37,49,54,58,62,74). Finding out which differences in the Gag epitopes between HLA alleles are associated with different outcomes of HIV-1 infection might therefore offer a vital clue for developing an effective HIV-1 vaccine.…”

Imunogenicidade da vacina de DNA quimérica LAMP-1/p55Gag do HIV-1 no período neonatal e efeito da imunização materna na resposta vacinal da prole de camundongos.

“…Atualmente, muitos estudos têm abordado a resposta de células T CD4+ e CD8+ aos peptídeos da Gag do HIV, considerando que a intensa resposta a Gag está associada com proteção (Betts et al, 2005;Price et al, 2009) e com o controle da viremia durante a infecção (Rolland et al, 2008;Huang et al, 2008;Serwanga et al, 2009). Outros fatores corroboram com a seleção da proteína Gag na composição da vacina como por exemplo, a característica de ser um gene relativamente conservado entre as diversas classes e subclasses do HIV-1, além do fato de promover ampla resposta cruzada antiGag entre pacientes infectados por subclasses diferentes de HIV-1 (Bertoletti et al, 1997;Norris et al, 2004).…”

Estudo da imunogenicidade da vacina de DNA quimérica LAMP/gag do HIV-1 em sítios de mucosa de camundongos imunizados no período neonatal.

“…Estudos de infecção por HIV têm relatado que a resposta de células T CD4+ e CD8+ aos peptídeos da GAG do HIV está associada com proteção (Betts et al, 2005;Price et al, 2009) e o controle da viremia durante a infecção (Rolland et al, 2008;Huang et al, 2008;Serwanga et al, 2009). Outros fatores que reforçam a escolha da proteína GAG na composição da vacina é por se tratar de um gene relativamente conservado entre as diversas classes e subclasses do HIV-1, permitindo resposta anti-GAG mesmo entre pacientes infectados por diferentes subclasses de HIV-1 (Norris et al, 2004).…”