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Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients.

ABSTRACT: Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1(+)) and HIV-2(+) individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2(+) patients, despite the reduced viremia (undetectable to 2.6 × 10(4) RNA copies/ml). However, tat mRNA transcripts were observed at significantly lower levels in HIV-2(+) patients, suggesting that the rate of de novo infection is decreased in these patients. Our data also reveal a direct relationship of gag and tat transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2(+) patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2(+) patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection.

SUBMITTER: Soares RS

PROVIDER: S-EPMC3067805 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients.

Soares Rui S RS Tendeiro Rita R Foxall Russell B RB Baptista António P AP Cavaleiro Rita R Gomes Perpétua P Camacho Ricardo R Valadas Emília E Doroana Manuela M Lucas Margarida M Antunes Francisco F Victorino Rui M M RM Sousa Ana E AE

Journal of virology 20101215 5

Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1(+)) and HIV-2(+) individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transc ...[more]

PMID: 21159859

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Project description:Prior hypothesis-driven studies identified immunophenotypic characteristics associated with the control of HIV replication without antiretroviral therapy (HIV controllers) as well as with the degree of CD4 T-cell recovery during ART. We hypothesized that an unbiased 'discovery-based' approach might identify novel immunologic characteristics of these phenotypes.We performed immunophenotyping on four 'aviremic' patient groups: HIV controllers (n?=?98), antiretroviral-treated immunologic nonresponders (CD4?<?350; n?=?59), antiretroviral-treated immunologic responders (CD4?>?350, n?=?142), and as a control group HIV-negative adults (n?=?43). We measured levels of T-cell maturation, activation, dysfunction, senescence, functionality, and proliferation.Supervised learning assessed the relative importance of immune parameters in predicting clinical phenotypes (controller, immunologic responder, or immunologic nonresponder). Unsupervised learning clustered immune parameters and examined if these clusters corresponded to clinical phenotypes.HIV controllers were characterized by high percentages of HIV-specific T-cell responses and decreased percentages of cells expressing human leukocytic antigen-antigen D related in naive, central memory, and effector T-cell subsets. Immunologic nonresponders were characterized by higher percentages of CD4 T cells that were TNF?+ or INF?+, higher percentages of activated naive and central memory T cells, and higher percentages of cells expressing programmed cell death protein 1. Unsupervised learning found two distinct clusters of controllers and two distinct clusters of immunologic nonresponders, perhaps suggesting different mechanisms for the clinical outcomes.Our discovery-based approach confirmed previously reported characteristics that distinguish aviremic individuals, but also identified novel immunologic phenotypes and distinct clinical subpopulations that should lead to more focused pathogenesis studies that might identify targets for novel therapeutic interventions.

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Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients.

Publications

Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients.

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