4th International AIDS Society Conference on HIV Pathogenesis and Treatment


Sydney, Australia - July 22 - 25, 2007

NAÏVE CD4+ T CELL HOMEOSTASIS DURING HIV INFECTION

IAS Conf HIV Pathog Treat 2007 Jul 22-25;4th: Abstract No. MOAA1LB

Rickabaugh T.M.1, Kilpatrick R.2, Fauce S.R.3, Hultin L.1, Hultin P.1, Hausner M.A.1, Effros R.B.3, Detels R.2, Phair J.4, Jamieson B.D.1
1University of California, David Geffen School of Medicine, Los Angeles, United States, 2University of California, School of Public Health, Los Angeles, United States, 3University of California, Department of Pathology and Laboratory Medicine, Los Angeles, United States, 4Northwestern University, Feinberg School of Medicine, Chicago, United States

OBJECTIVES: To determine the effect of HIV infection and HAART treatment on naïve CD4+ T-cell homeostasis.

METHODS: PBMC from seronegative and seropositive individuals were phenotyped and sorted into two naïve CD4+ T-cell subsets defined by CD45RA and CD31. Genomic DNA was extracted from the sorted cells and used to measure telomere length by Real-Time PCR.

RESULTS: We and others have recently shown that naïve CD4+ T-cells maintain homeostasis by low level proliferation while still retaining a naïve phenotype. In general, the so-called “undifferentiated” naïve cells undergoing minimal proliferation express CD45RA, and CD31, while their “differentiated” naïve cell progeny lose CD31 expression. Here we present our results from a cross-sectional study, which demonstrate that HAART-naïve HIV+ participants within 1-3 years of infection have significantly fewer undifferentiated (CD45RA+/CD31+) and differentiated (CD45RA+/CD31-) naïve CD4+ T-cells than seronegative controls (p=0.002). Real-Time PCR analysis on naïve CD4+ T-cells from the same HIV+ participants revealed telomere lengths that were similar to those from seronegative individuals 30 years older. In a longitudinal study, immunophenotyping of cells from HIV+ participants who were on HAART for two years showed reconstitution of the CD4+/CD45RA+/CD31+ subset (p=0.20), suggestive of new thymic output. However, the more differentiated naïve (CD4+/CD45RA+/CD31-) subset failed to reconstitute to levels observed in seronegative controls (p=0.001).

CONCLUSIONS: Reduced numbers of naïve CD4+ T-cells and shortened telomeres suggest that HIV infection mimics aging in the naïve CD4+ T-cell compartment. Our results also indicate that HAART may not be able to fully reverse this effect. As aging is known to detrimentally affect T-cell function and to increase susceptibility to infectious disease, our data provide a possible mechanism by which adaptive immune responses to HIV and to opportunistic infections are hampered. These results have important implications both for HIV+ individuals on HAART and for the increasing population of older HIV+ individuals.

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2007-07-22
MOAA1LB
Immune Activation in HIV Pathogenesis

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