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 )

Abstract

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), SHIV CHN19 , was generated with a primary, non-syncytium-inducing HIV-1 subtype C envelope from a Chinese strain in the background of SHIV 33 . Unlike R5-tropic SHIV 162 , SHIV CHN19 was not found to replicate in rhesus CD4 ؉ T lymphocytes. SHIV CHN19 does, however, replicate in CD4 ؉ T lymphocytes of pig-tailed macaques (Macaca nemestrina). The observed replication competence of SHIV CHN19 requires the full tat/rev genes and partial gp41 region derived from SHIV 33 . To evaluate in vivo infectivity, SHIV CHN19 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 SHIV CHN19 , 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 10 3 to 10 5 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 SHIV CHN19 isolated from P4 animals. In addition, the infectivity of SHIV CHN19 in rhesus peripheral blood mononuclear cells was also increased after in vivo passages. Our data indicate that SHIV CHN19 has adapted well to grow in macaque cells. This established R5-tropic SHIV CHN19 /macaque model would be very useful for HIV-1 subtype C vaccine and pathogenesis studies.

Divergent Host Responses during Primary Simian Immunodeficiency Virus SIVsm Infection of Natural Sooty Mangabey and Nonnatural Rhesus Macaque Hosts

“…Repeated serial passage of SIV in macaques will select for highly adapted viruses with uniformly high replicative capacity in the new host and, along with this, an attendant rapid course of disease (6,58). However, our observation that SIVsm that has never been passaged in an RM can replicate to high levels and cause disease in this new species demonstrates that neither serial passaging nor an extensive period of SIV adaptation in the new host is required to cause AIDS.…”

Molecularly Cloned SHIV-1157ipd3N4: a Highly Replication- Competent, Mucosally Transmissible R5 Simian-Human Immunodeficiency Virus Encoding HIV Clade Cenv

“…Although several non-clade B HIV-1 envelope-based SHIV chimeric constructs have been described so far (8,10,30,41,58), none of them has been reported to be mucosally transmissible or to induce signs of disease in rhesus macaques, the most commonly used nonhuman primate in AIDS research. Here we report the construction of SHIV-1157ipd3N4.…”

Neuronal Apoptosis Is Mediated by CXCL10 Overexpression in Simian Human Immunodeficiency Virus Encephalitis

“…10 One broad explanation frequently advocated explaining the loss of neurons in this disease is that cellular and/or viral proteins released from the infected cells have a direct toxic effect on the neurons. [11][12][13][14][15][16][17][18] Because all parenchymal brain cells are known to express chemokine receptors, 19 and because expression of chemokines becomes dysregulated and frequently overexpressed during central nervous system (CNS) inflammation, it is possible that overexpressed chemokines in the HIV-infected brain may orchestrate the degenerative neuronal changes. 20 In earlier studies aimed at exploring factors contributing to encephalitis caused by simian human immunodeficiency virus (SHIV) in the rhesus macaque model of HIV encephalopathy, we performed chemokine microarray analysis on the brains of infected macaques with and without SHIV-E.…”