The immunologic and virologic characteristics of 37 HIV-infected long-term non-progressors (LTNPs) were studied; in these patients, disease has not progressed despite 7 to 20 years of documented HIV infection. Viral load was significantly lower in peripheral blood and lymph nodes of LTNPs compared with progressors. Histopathologic examination of lymph nodes obtained from non-progressors did not reveal follicular involution, lymphocyte depletion, or other architectural disruptions characteristic of progressive disease. However, heterogeneity among non-progressors was the rule, with patterns ranging from follicular hyperplasia with abundant trapping of extracellular virions to quiescence with only primary follicles evident and little virus trapping. HIV-specific cytotoxicity against gag proteins was consistently observed in peripheral blood mononuclear cells (PBMC) of LTNPs. Potent CD8 cell-associated HIV suppressor activity was present in the peripheral blood of most LTNPs. Proliferative responses to a variety of stimuli were preserved in PBMC of LTNPs. Sera from LTNPs had higher titers of neutralizing antibodies to laboratory and primary HIV isolates compared with sera from progressors. In addition, low titers of neutralizing antibodies to autologous virus isolates were found almost exclusively in LTNPs. A significantly higher percentage of LTNPs compared with progressors were heterozygous for the defective CCR5 gene (CCR5-delta32), that is associated with slower progression of HIV disease. We tested the hypothesis that CCR5 heterozygotes might, by virtue of reduced availability of functional HIV co-receptors, constitute a homogeneous subgroup of LTNPs with the lowest viral loads and highest CD4+ T-cell counts. However, CCR5 heterozygotes were indistinguishable from CCR5 wild-type non-progressors with regard to all measured immunologic and virologic parameters. No significant mutations other than CCR5-delta32 were found in the CCR5 or CXCR4 open reading frames, which were sequenced from 17 LTNPs. A correlation was found between the status of an NcoI polymorphism in the TNF-beta gene and levels of plasma viremia among LTNPs. In addition, a polymorphism in the CR1 gene appears to be significantly over-represented among non-progressors. These data highlight the fact that multiple mechanisms may be operative in the determination of the state of non-progression with HIV infection.
