DIFFERENTIAL REPLICATION AND PATHOGENIC EFFECTS OF HIV-1 AND HIV-2 INMACACA-NEMESTRINA

Objective: HIV-1 and HIV-2 isolates representing various geographic re gions and distinct viral subtypes were examined for their ability to e stablish both in vitro and in vivo productive infections of Macaca nem estrina (pigtail macaque) peripheral blood mononuclear cells. Methods: Animals were inoculated with either autologous cell-associated or cel l-free viral preparations of selected isolates. HIV-specific immune re sponsiveness, hematologic changes, genetic variation, and virus burden were monitored as delineators of HIV pathogenesis. Results: HIV-2 rep lication in vitro and in vivo correlated with nascent antigen producti on and rising viral titers as determined by infectious center assays. Infection was detectable by polymerase chain reaction amplification of proviral sequences in macaque cells as early as 1 week postinoculatio n. Two distinct patterns of CD4+ cell depletion induced by HIV-2 infec tion were observed during the first month postinoculation and characte rized by a moderate loss sustained through 20 weeks postinoculation or a substantial loss maintained long-term (> 90 weeks). Identity betwee n inoculating viral stocks and subsequent viral isolates from animals was established comparatively by limited sequence analysis of specific domains within the HIV-2 pol and env genes. In contrast, replication of HIV-1 isolates was limited or only semipermissive in vitro. Intrave nous inoculation of HIV-1 field isolates, using conditions successful for HIV-2 (for example, identical viral titers), failed to establish a productive viral infection leading to seroconversion or fluctuations in hematologic cell markers. Infection with a high-titer inoculum of a laboratory-adapted HIV-1 strain in vivo, as demonstrated by polymeras e chain reaction analysis, produced seroconversion in the absence of o vert viral replication or hematologic variations in one out of four an imals. Conclusions: This system provides for multifaceted modeling of HIV pathogenesis, primarily with HIV-2 and potentially with HIV-1/-2 c himerics, in support of immunotherapeutic developments and critical ev aluation of intervention practices.