We have studied the immunologic and virologic characteristics of 33 HIV-infected long-term non-progressors (LTNPs) whose disease has not progressed over periods from 7 to 20 years. Viral load was significantly lower in peripheral blood and lymph nodes of LTNPs compared with progressors; however, significant heterogeneity was evident in these measures among non-progressors as was some overlap 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. 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. CD4+ T cells from LTNPs as well as nearly all patients tested with progressive disease were able to respond ex vivo to interleukin-2 by normal activation of the Jak/STAT signalling pathway. Lymph node MC from LTNPs exhibit incomplete expression of rev/nef HIV mRNAs, possibly due to mutations within key HIV splice acceptor sites. A significantly higher percentage of LTNPs compared with progressors were heterozygous for the defective CCR5 gene (CCR5-(32) (38% vs. 22%, p = 0.05). No significant mutations other that CCR5-(32 were found in the CCR5 or CXCR4 open reading frames which were sequenced from 17 LTNPs. 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. These data highlight the fact that multiple mechanisms may be operative in the determination of the state of non-progression with HIV infection.
