17th International AIDS Conference Mexico City, Mexico - August 13 - 18, 2008

RECOMBINATION RATES ARE HIGHER IN TISSUES SHOWING SIGNIFICANT MACROPHAGE INFILTRATION AND VARY AMONG ENV, NEF AND LTR DOMAINS

Int Conf AIDS. 2008 Aug 13-18;17 Abstract No. MOAA0304

M.S. McGrath ¹, S.L. Lamers², D. Galligan¹, S. Granier², T. deOliveira³, M. Salemi^4
1AIDS and Cancer Specimen Resource (ACSR), University of California, San Francisco (UCSF), Department of Medicine, San Francisco, United States, ²BioInfoExperts Inc., Gainesville, United States, ³South African National Bioinformatics Institute, Cape Town, South Africa, ⁴University of Florida, Department of Pathology, Immunology, and Laboratory Medicine, Gainesville, United States

BACKGROUND: Recombination between intra-host HIV-1 quasispecies has been implicated in immune evasion, the acquisition of drug-resistance mutations, and the switch of co-receptor usage. However, no data are available to date about the extent of recombination in different lymphoid and non-lymphoid tissues with abnormal histopathology due to HIV-associated diseases.

METHODS: 1500+ HIV-1 genomes, spanning env-LTR, were sequenced from 50+ lymphoid and non-lymphoid tissues. The tissues, obtained from the AIDS and Cancer Specimen Resource (ACSR), were harvested post-mortem from patients who died of various AIDS-associated illnesses. Tissues were classified as abnormal or normal by histology examination and stained with CD68, MAC 387 and p24. Split-decomposition analysis using the Neighbor-Net (NNet) algorithm was utilized in combination with the PHI-test in order to identify recombinant sequences. Recombinants were then examined using bootscanning and a genetic algorithm (GARD) to map putative breakpoints.

RESULTS: NNet sequence analysis frequently revealed complex networks in sequences as well as a significant p-value for recombination in the PHI-test. Recombinant sequences within the nef and LTR genomes were significantly lower than in env. While few or no recombinant sequences were usually detected in the env domains of normal tissues, up to 50% of HIV-1 sequences amplified from abnormal tissues, extensively infiltrated with HIV-1 infected macrophages, were recombinants. In general, no positive selection was detected, but recombinant sequences from meninges showed significantly weaker purifying selection than non recombinant ones.

CONCLUSIONS: The presence of extensive viral recombination in abnormal tissues with significant macrophage infiltration suggests that macrophages could be the main reservoir for the generation of HIV-1 intra-patient recombinant sequences in vivo. Recombination in the meninges, in particular, may lead to the emergence of viral strains with relaxed selective constraints characterized by a higher potential to explore the sequence space. Therefore, successful viral eradication may require novel therapeutic approaches targeting HIV-infected tissue macrophages.

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2008-08-13
MOAA0304

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