HIV-1-Specific T Cell Precursors with High Proliferative Capacity Correlate with Low Viremia and High CD4 Counts in Untreated Individuals

Abstract

Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We focused on the quantification of Ag-specific T cell precursors with high proliferative capacity (PHPC) using a peptide-based cultured IFN-γ ELISPOT assay (PHPC assay), which has been shown to identify expandable memory T cells. To determine which responses correlate with viral suppression and positive immunologic outcome, PBMC from 32 chronically untreated HIV-1-infected individuals were evaluated in response to peptide pools, representing the complete HIV-1 Gag, Nef, and Rev proteins, by PHPC and IFN-γ ELISPOT assay, which instead identifies effector T cells with low proliferative capacity. High magnitude of Gag-specific PHPC, but not ELISPOT, responses significantly correlated with low plasma viremia, due to responses directed toward p17 and p15 subunits. Only Gag p17-specific PHPC response significantly correlated with high CD4 counts. Analysis of 20 additional PBMC samples from an independent cohort of chronically untreated HIV-1-infected individuals confirmed the correlation between Gag p17-specific PHPC response and either plasma viremia (inverse correlation) or CD4 counts (direct correlation). Our results indicate that the PHPC assay is quantitatively and qualitatively different from the ELISPOT assay, supporting that different T cell populations are being evaluated. The PHPC assay might be an attractive option for individual patient management and for the design and testing of therapeutic and prophylactic vaccines.

Identification of Surrogates and Correlates of Protection in Protective Immunity againstMycobacterium bovisInfection Induced in Neonatal Calves by Vaccination withM. bovisBCG Pasteur andM. bovisBCG Danish

“…A number of studies have shown significant correlations between protective immunity and cultured ELISPOT responses (9,17,30,36). Although we have not shown definitively for cattle that the cultured ELISPOT assay measures only central memory, and not effector, T cell responses (due to a lack of specific reagents for central memory T cells in cattle, such as CCR7), a recent study revealed that PPD-specific cultured ELISPOT responses in humans were principally those of central memory T cells, as depletion of these cells ablated the cultured ELISPOT response (30).…”

Simian Immunodeficiency Virus (SIV)-Specific CD8+T-Cell Responses in Vervet African Green Monkeys Chronically Infected with SIVagm

“…In SIV-challenged RM, pathogenicity studies and vaccine trials have suggested that robust, multifunctional CD8 ϩ T-cell responses are correlated with a less-pathogenic course of infection (36,67). It is evident that the quantity and the quality of immune responses are critical for more-efficient containment of AIDS virus infections (9,40,67). The assays performed in the present study did not detect a qualitative difference in the cytokine pattern of the CD8 ϩ T-cell responses between the RM and vervet AGM chronically infected with SIV but did detect a lower number of responding CD8 ϩ T cells in the vervet AGM.…”

Strong HIV-Specific CD4 + and CD8 + T-Lymphocyte Proliferative Responses in Healthy Individuals Immunized with an HIV-1 DNA Vaccine and Boosted with Recombinant Modified Vaccinia Virus Ankara Expressing HIV-1 Genes

“…In a South African cohort of HIV-infected individuals, proliferation showed a significant inverse correlation with viral load, while cytokine production and degranulation did not (5). Ca-larota et al (2) recently also showed that the presence of antigen-specific T-cell precursors with high proliferative capacity was associated with HIV-1 control and preservation of CD4 counts. Additionally, T-cell proliferation has been associated with reduced HIV acquisition in Kenyan female sex workers (12).…”