Enhanced Infectivity of an R5-Tropic Simian/Human Immunodeficiency Virus Carrying Human Immunodeficiency Virus Type 1 Subtype C Envelope after Serial Passages in Pig-Tailed Macaques (Macaca nemestrina)

摘要

The increasing prevalence of human immunodeficiency virus type 1 (HIV-1) subtype C infection worldwide calls for efforts to develop a relevant animal model for evaluating strategies against the transmission of the virus. A chimeric simian/human immunodeficiency virus (SHIV), SHIVCHN19, was generated with a primary, non-syncytium-inducing HIV-1 subtype C envelope from a Chinese strain in the background of SHIV33. Unlike R5-tropic SHIV162, SHIVCHN19 was not found to replicate in rhesus CD4+ T lymphocytes. SHIVCHN19 does, however, replicate in CD4+ T lymphocytes of pig-tailed macaques (Macaca nemestrina). The observed replication competence of SHIVCHN19 requires the full tat/rev genes and partial gp41 region derived from SHIV33. To evaluate in vivo infectivity, SHIVCHN19 was intravenously inoculated, at first, into two pig-tailed and two rhesus macaques. Although all four animals became infected, the virus replicated preferentially in pig-tailed macaques with an earlier plasma viral peak and a faster seroconversion. To determine whether in vivo adaptation would enhance the infectivity of SHIVCHN19, passages were carried out serially in three groups of two pig-tailed macaques each, via intravenous blood-bone marrow transfusion. The passages greatly enhanced the infectivity of the virus as shown by the increasingly elevated viral 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 postinoculation and had a decline in CD4/CD8 T-cell ratio during the early phase of infection. In P4 animals, a profound depletion of CD4 T cells in the lamina propria of the jejunum was observed. Persistent plasma viremia has been found in most of the infected animals with sustained viral loads ranging from 103 to 105 per ml up to 6 months postinfection. Serial passages did not change the viral phenotype as confirmed by the persistence of the R5 tropism of SHIVCHN19 isolated from P4 animals. In addition, the infectivity of SHIVCHN19 in rhesus peripheral blood mononuclear cells was also increased after in vivo passages. Our data indicate that SHIVCHN19 has adapted well to grow in macaque cells. This established R5-tropic SHIVCHN19/macaque model would be very useful for HIV-1 subtype C vaccine and pathogenesis studies.