The role of HIV-1 envelope glycoproteins in the pathogenesis of HIV/AIDS: A study in a nonhuman primate model

The human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of HIV/AIDS. HIV-1 causes AIDS by depletion of CD4+ T lymphocytes in infected individuals. The identification of viral and host factors involved in HIV-1 pathogenesis is paramount in the development of novel antiretroviral drugs and an effective AIDS vaccine. Pathogenic simian human immunodeficiency viruses (SHIVs) expressing HIV-1 envelope glycoproteins can cause severe CD4 + T-cell depletion and AIDS-like illnesses in infected rhesus macaques and other nonhuman primates. Therefore, SHIV infection of nonhuman primates is an excellent model to study HIV/AIDS pathogenesis. In the thesis presented, we explored the in vivo role of the HIV-1 exterior envelope glycoproteins in pathogenesis, utilizing the SHIV-macaque model.; To address the role of HIV-1 envelope glycoproteins in pathogenesis, the SHIV-HXBc2P 3.2 molecular clone was constructed. This virus expresses the HIV-1 envelope glycoproteins of the pathogenic SHIV-HXBc2 variant (KU-1), which differs from the non-pathogenic parent SHIV-HXBc2 in only twelve amino acid residues. Compared to the parental virus, the envelope glycoproteins of SHIV-HXBc2P 3.2 were significantly more resistant to neutralizing antibodies and responsible for increased viral replication capacity in vitro and in vivo. SHIV-HXBc2P 3.2 caused a profound loss of CD4+ T cells within 2 weeks of infection in all three inoculated rhesus macaques. Approximately two years after infection, two of the three infected animals developed AIDS-like illnesses.; One of the two SHIV-HXBc2P 3.2-infected animals that succumbed to AIDS developed neurologic disease. To investigate the potential role of HIV-1 envelope glycoproteins in neuropathogeneis, a brain isolate (3.2N) was generated from the diseased animal. In contrast to the original SHIV-HXBc2P 3.2 virus, 3.2N is both macrophage-tropic and sensitive to broadly neutralizing antibodies. We found that the envelope glycoproteins contributed significantly to the brain isolate's phenotype.; The role of clade C envelope glycoproteins in CD4+ T-cell depletion was also addressed by constructing a SHIV expressing the envelope glycoproteins of a primary dual-tropic R5/X4 clade C HIV-1. Serial in vivo transmission of this virus resulted in acute CD4+ T-cell depletion in rhesus macaques, which suggests an important role for R5/X4 clade C envelope glycoproteins in pathogenesis. Thus, the results of studies utilizing the SHIV-macaque model system presented in this thesis strongly suggest a critical role for HIV-1 envelope glycoproteins in the pathogenesis of HIV/AIDS.