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2.  Short Communication: CD8+ T Cell Polyfunctionality Profiles in Progressive and Nonprogressive Pediatric HIV Type 1 Infection 
AIDS Research and Human Retroviruses  2011;27(9):1005-1012.
Abstract
Pediatric HIV-1 infection is characterized by rapid disease progression and without antiretroviral therapy (ART), more than 50% of infected children die by the age of 2 years. However, a small subset of infected children progresses slowly to disease in the absence of ART. This study aimed to identify functional characteristics of HIV-1-specific T cell responses that distinguish children with rapid and slow disease progression. Fifteen perinatally HIV-infected children (eight rapid and seven slow progressors) were longitudinally studied to monitor T cell polyfunctionality. HIV-1-specific interferon (IFN)-γ+ CD8+ T cell responses gradually increased over time but did not differ between slow and rapid progressors. However, polyfunctional HIV-1-specific CD8+ T cell responses, as assessed by the expression of four functions (IFN-γ, CD107a, TNF-α, MIP-1β), were higher in slow compared to rapid progressors (p=0.05) early in infection, and was associated with slower subsequent disease progression. These data suggest that the quality of the HIV-specific CD8+ T cell response is associated with the control of disease in children as has been shown in adult infection.
doi:10.1089/aid.2010.0227
PMCID: PMC3332389  PMID: 21288139
3.  Impairment of CD1d-Restricted Natural Killer T Cells in Chronic HIV Type 1 Clade C Infection 
Abstract
Recent studies suggest that natural killer T (NKT) cells play a role in early antiviral pathogenesis and are rapidly depleted in chronic human immunodeficiency virus type 1 (HIV-1) clade B infection. We aimed to characterize the phenotypic and functional characteristics of NKT cells in HIV-1 clade C-infected Africans at different stages of HIV-1 disease. NKT cell frequencies, subsets, and ex vivo effector functions were assessed using multiparametric flow cytometry in a cross-sectional analysis of cryopreserved peripheral blood mononuclear cells from a cohort of 53 HIV-1 clade C chronically infected South African adults with CD4 T cell counts ranging from 94 to 839 cells/μl. We observed a significant decline of NKT cell numbers in advanced HIV-1 disease as well as activation and functional impairment of NKT cells in individuals with low CD4 T cell counts. The loss of NKT cells was largely driven by a reduction in the CD4+ and CD4–CD8– NKT cell subsets in advanced disease. These findings demonstrate significant impairment of the NKT cell compartment in progressive HIV-1 clade C disease that might play an important role in the modulation of immune function in HIV-1 infection.
doi:10.1089/aid.2010.0237
PMCID: PMC3083726  PMID: 20942750
4.  IgG Subclass Profiles in Infected HIV Type 1 Controllers and Chronic Progressors and in Uninfected Recipients of Env Vaccines 
Abstract
We have studied IgG subclass responses to the HIV-1 proteins gp120, gp41, p24, and Tat in individuals who control their infection without using antiretroviral drugs (HIV-1 controllers; HC) or who progress to disease (chronic progressors; CP). We also measured IgG subclass titers to gp120 in vaccinated individuals. In all cases, the IgG1 subclass dominated the overall response to each antigen. The only IgG titer that differed significantly between the HC and CP groups was to the p24 Gag protein, which was higher in the HC group. IgG1 titers to both p24 and gp120 were significantly higher in the HC group, and IgG3 anti-gp120 antibodies, although rare, were detected more frequently in that group than in CP. Overall, significantly more patients had IgG2 antibodies to gp120 than to gp41. Antibodies to other IgG subclasses were infrequent and their frequency or titers did not differ between the two patient groups. Anti-gp41 and anti-Tat responses also did not correlate with immune control, and anti-Tat antibodies were infrequently detected. Although we found isotypic differences in IgG responses to HIV-1 antigens among vaccinees and the HC and CP individuals, there were no indications of differential TH1:TH2 polarization between the different groups.
doi:10.1089/aid.2009.0223
PMCID: PMC2864049  PMID: 20377426
5.  Alterations in Natural Killer Cell Receptor Profiles During HIV Type 1 Disease Progression Among Chronically Infected South African Adults 
Abstract
Recent studies suggest that innate immune responses by natural killer (NK) cells play a significant role in restricting human immunodeficiency virus type-1 (HIV-1) pathogenesis. Our aim was to characterize changes in NK cells associated with HIV-1 clade C disease progression. Here we used multiparametric flow cytometry (LSRII) to quantify phenotype and function of NK cells in a cross-sectional analysis of cryopreserved blood samples from a cohort of 41 chronically HIV-1-infected, treatment-naive adult South Africans. These individuals ranged in disease severity from early (CD4 count >500) to advanced HIV-1 disease (CD4 count <50). We found that the frequency of NK cells expressing KIR2DL1, an inhibitory receptor, and/or KIR2DS1, an activating receptor, tended to decrease with increasing HIV-1 viral load. We also discovered a significant increase (p < 0.05) in overall NK cell degranulation with disease progression. We found that acutely activated NK cells (CD69pos) were deficient in NKp46 expression ex vivo. In conclusion, we observed that with viremia and advanced HIV-1 disease, activated NK cells lack NKp46 expression, and KIR2DS1pos and/ or KIR2DL1pos NK cells are reduced in frequency. These findings suggest that modulation of receptor expression on NK cells may play a role in HIV-1 pathogenesis, and provide new insights on immunological changes in advanced HIV-1 disease.
doi:10.1089/aid.2009.0176
PMCID: PMC3111148  PMID: 20380481
6.  Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles 
Abstract
HIV-1 can evolve HLA-specific escape variants in response to HLA-mediated cellular immunity. HLA alleles that are common in the host population may increase the frequency of such escape variants at the population level. When loss of viral fitness is caused by immune escape variation, these variants may revert upon infection of a new host who does not have the corresponding HLA allele. Furthermore, additional escape variants may appear in response to the nonconcordant HLA alleles. Because individuals with rare HLA alleles are less likely to be infected by a partner with concordant HLA alleles, viral populations infecting hosts with rare HLA alleles may undergo a greater amount of evolution than those infecting hosts with common alleles due to the loss of preexisting escape variants followed by new immune escape. This hypothesis was evaluated using maximum likelihood phylogenetic trees of each gene from 272 full-length HIV-1 sequences. Recent viral evolution, as measured by the external branch length, was found to be inversely associated with HLA frequency in nef (p < 0.02), env (p < 0.03), and pol (p ≤ 0.05), suggesting that rare HLA alleles provide a disproportionate force driving viral evolution compared to common alleles, likely due to the loss of preexisting escape variants during early stages postinfection.
doi:10.1089/aid.2008.0208
PMCID: PMC2693345  PMID: 19327049
7.  Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles 
HIV-1 can evolve HLA-specific escape variants in response to HLA-mediated cellular immunity. HLA alleles that are common in the host population may increase the frequency of such escape variants at the population level. When loss of viral fitness is caused by immune escape variation, these variants may revert upon infection of a new host who does not have the corresponding HLA allele. Furthermore, additional escape variants may appear in response to the nonconcordant HLA alleles. Because individuals with rare HLA alleles are less likely to be infected by a partner with concordant HLA alleles, viral populations infecting hosts with rare HLA alleles may undergo a greater amount of evolution than those infecting hosts with common alleles due to the loss of preexisting escape variants followed by new immune escape. This hypothesis was evaluated using maximum likelihood phylogenetic trees of each gene from 272 full-length HIV-1 sequences. Recent viral evolution, as measured by the external branch length, was found to be inversely associated with HLA frequency in nef (p<0.02), env (p<0.03), and pol (p≤0.05), suggesting that rare HLA alleles provide a disproportionate force driving viral evolution compared to common alleles, likely due to the loss of preexisting escape variants during early stages postinfection.
doi:10.1089/aid.2008.0208
PMCID: PMC2693345  PMID: 19327049
8.  Fine specificity and cross-clade reactivity of HIV-1 Gag-specific CD4+ T cells 
Despite growing evidence that HIV-1-specific CD4+ T helper (Th) cells may play a role in the control of viremia, discrete Th cell epitopes remain poorly defined. Furthermore, it is not known whether Th cell responses generated using vaccines based on clade B virus sequences will elicit immune responses that are effective in regions of the world where non-clade B viruses predominate. To address these issues we isolated CD4+ T cell clones from individuals with vigorous HIV-1-specific Th cell responses and identified the minimum epitopes recognized. The minimum peptide length required for induction of CD4+ T cell proliferation, IFN-γ secretion, and cytolytic activity ranged from 9 to 16 amino acids in the five epitopes studied. Cross-clade recognition of the defined epitopes was examined for variant peptides from clades A, B, C, D, and AE. Over half the variant epitopes (17 of 32) exhibited impaired recognition, defined as less than 50% of the IFN-γ secretion elicited by B clade consensus sequence. There was no evidence for antagonistic activity mediated by the variant peptides, and despite strong responses there was no escape of autologous virus from Th responses in the epitopes we studied. Abrogated recognition of variant CD4+ T cell epitopes presents a potential obstacle to vaccine development.
doi:10.1089/088922204322996554
PMCID: PMC2553686  PMID: 15117455

Results 1-8 (8)