Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serialpassages in pig-tailed macaques (Macaca nemestrina)

The increasing prevalence of human immunodeficiency virus type, 1 (HIV-1) s ubtype C infection worldwide calls for efforts to develop a relevant animal model for evaluating strategies against the transmission of the virus. A c himeric simian/human immunodeficiency virus (SHIV), SHIVCHN19, was generate d with a primary, non-syncytium-inducing HIV-1 subtype C envelope from a Ch inese strain in the background of SHIV33. Unlike R5-tropic SHIV162, SHIVCHN 19 was not found to replicate in rhesus CD4(+) T lymphocytes. SHIVCHN19 doe s, however, replicate in CD4(+) T lymphocytes of pig-tailed macaques (Macac a nemestrina). The observed replication competence of SHIVCHN19 requires th e full tat/rev genes and partial gp41 region derived from SHIV33. To evalua te in vivo infectivity, SHIVCHN19 was intravenously inoculated, at first, i nto two pig-tailed and two rhesus macaques. Although all four animals becam e infected, the virus replicated preferentially in pig-tailed macaques,vith an earlier plasma viral peak and a faster seroconversion. To determine whe ther in vivo adaptation mould enhance the infectivity of SHIVCHN19, passage s were carried out serially in three groups of two pig-tailed macaques each , via intravenous blood-bone marrow transfusion. The passages greatly enhan ced the infectivity of the virus as shown by the increasingly elevated vira l loads during acute infection in animals with each passage. Moreover, the doubling time of plasma virus during acute infection became much shorter in passage 4 (P4) animals (0.2 day) in comparison to P1 animals (1 to 2 days) . P2 to P4 animals all became seropositive around 2 to 3 weeks postinoculat ion and had a decline in CD4/CD8 T-cell ratio during the early phase of inf ection. In P4 animals, a profound depletion of CD4 T cells in the lamina pr opria of the jejunum was observed. Persistent plasma viremia has been found in most of the infected animals with sustained viral loads ranging from 10 (3) to 10(5) per ml up to 6 months postinfection. Serial passages did not c hange the viral phenotype as confirmed by the persistence of the R5 tropism of SHIVCHN19 isolated from P4 animals. In addition, the infectivity of SHI V,,,, in rhesus peripheral blood mononuclear cells was also increased after in vivo passages. Our data indicate that SHIVCHN19 has adapted well to gro w in macaque cells. This established R5-tropic SHIVCHN19/macaque model woul d be very useful for HIV-1 subtype C vaccine and pathogenesis studies.