Despite the dominant role of R5 viruses in HIV-1 transmission and early infection, in about 50% of patients, X4 viruses emerge late in infection, coincident with the decline in circulating CD4+ T cells and precedes the onset of AIDS. Infections of rhesus macaques with X4-specific SHIVSF33A and R5-specific SHIVSF162P3 were performed to address the underlying basis for the apparent preferential transmission and early infection of R5 viruses. Data showed that there is no intrinsic barrier to the transmission and dissemination of X4-SHIVsF33A, but that R5-SHIVSF162P3 dominated shortly after infection. Administration of anti-CD8 antibodies at the time of R5 dominance resulted in the emergence of the X4- SHIVSF33A, suggesting that the X4 virus is more susceptible to CD8+ T cell mediated immune control. A hypothesis/model, based on the premise of target cell competition, is proposed in which preferential infection and replication of R5-SHIVSF162P3 in tissue macrophages explains for its dominance in the dually-infected macaques. Several questions/issues arose as a result of these findings in the co-infected macaques and the model proposed, and form the basis of the present continuation grant application. First, although we favor CoR usage as the determining factor for R5-SHIVSF162P3 dominance, it is conceivable that the reduced fitness and inherent susceptibility to immune control of X4-SHIVSF33A in the dually infected macaques are due to other factors in the virus genetic background. V3 loop isogenic viruses that differ in CoR usage therefore will be used for infection of macaques to further define the influence of viral tropism on pathogenesis and viral dominance in vivo (Specific Aim #1). Second, to test our hypothesis which is based on differential macrophage tropism, we propose to characterize the cells producing X4-SHIVSF33A and R5-SHIVSF162P3 during the course of infection in singly as well as dually infected macaques (Specific Aim #2). Of particular interest will be the identification of the virus populations residing in the macrophage and T cell pools of dually infected macaques. Third, the nature of the CD8+ T cell mediated response responsible for virus suppression in the X4- and R5-SHIV infected animals is not known. This is particularly pertinent in light of the fact that the infected animals undergo a rapid, profound loss of CD4+ T cells, raising questions as to the functionality of their CD8+ T cells. Thus, in Specific Aim # 3, we propose to examine and compare the development, maintenance and effectiveness of CD8+ T cell response elicited in X4-, R5- and dually-infected macaques that suffer rapid and severe loss of different CD4+ T cell subpopulations. Lastly, the question of whether the use of anti-viral agents directed at the CCR5 coreceptor in vivo would facilitate the selection of X4-utilizing viruses remains unresolved. The dual infection animal model described here provides a unique opportunity to evaluate whether administration of CCR5 inhibitors at the time of R5 dominance will lead to the re-emergence of the X4 virus (Specific Aim #4).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046980-09
Application #
7369784
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2000-03-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
9
Fiscal Year
2008
Total Cost
$651,692
Indirect Cost
Name
Aaron Diamond AIDS Research Center
Department
Type
DUNS #
786658872
City
New York
State
NY
Country
United States
Zip Code
10016
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Harbison, Carole; Zhuang, Ke; Gettie, Agegnehu et al. (2014) Giant cell encephalitis and microglial infection with mucosally transmitted simian-human immunodeficiency virus SHIVSF162P3N in rhesus macaques. J Neurovirol 20:62-72
Tsai, Lily; Tasovski, Ivan; Leda, Ana Rachel et al. (2014) The number and genetic relatedness of transmitted/founder virus impact clinical outcome in vaginal R5 SHIVSF162P3N infection. Retrovirology 11:22
Ren, Wuze; Mumbauer, Alexandra; Gettie, Agegnehu et al. (2013) Generation of lineage-related, mucosally transmissible subtype C R5 simian-human immunodeficiency viruses capable of AIDS development, induction of neurological disease, and coreceptor switching in rhesus macaques. J Virol 87:6137-49
Ren, Wuze; Mumbauer, Alexandra; Zhuang, Ke et al. (2013) Mucosal transmissibility, disease induction and coreceptor switching of R5 SHIVSF162P3N molecular clones in rhesus macaques. Retrovirology 10:9
Shakirzyanova, Madina; Tsai, Lily; Ren, Wuze et al. (2012) Pathogenic consequences of vaginal infection with CCR5-tropic simian-human immunodeficiency virus SHIVSF162P3N. J Virol 86:9432-42
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Zhuang, Ke; Finzi, Andres; Tasca, Silvana et al. (2011) Adoption of an ""open"" envelope conformation facilitating CD4 binding and structural remodeling precedes coreceptor switch in R5 SHIV-infected macaques. PLoS One 6:e21350
Ren, Wuze; Tasca, Silvana; Zhuang, Ke et al. (2010) Different tempo and anatomic location of dual-tropic and X4 virus emergence in a model of R5 simian-human immunodeficiency virus infection. J Virol 84:340-51
Shakirzyanova, Madina; Ren, Wuze; Zhuang, Ke et al. (2010) Fitness disadvantage of transitional intermediates contributes to dynamic change in the infecting-virus population during coreceptor switch in R5 simian/human immunodeficiency virus-infected macaques. J Virol 84:12862-71

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