Understanding the reasons why SIV-infected sooty mangabeys (SMs) remain healthy despite high viremia is a key unanswered question in contemporary AIDS research, with important ramifications in terms of HIV pathogenesis, therapy, and vaccines. In recent studies, we have sorted central memory CD4+ T cells (TCM) and effector-memory CD4+ T cells (CD4+ TEM) from SIV-infected SMs and rhesus macaques (RMs), and that, while CD4+ TEM were similarly infected in both species, CD4+ TCM of SMs show significantly (>1 log) fewer SIV-DNA copies in vivo than CD4+ TCM of RMs. Based on this result, we hypothesize that protection of CD4+ TCM from virus infection is a key mechanisms by which SIV-infected SMs avoid CD4+ T cell depletion, chronic immune activation, and progression to AIDS. To test this hypothesis we will expand upon this previous work and propose a series of studies that will clarify the main features of in vivo and in vitro SIV infection in CD4+ TCM of both SMs and RMs, and elucidate the mechanisms by which CD4+ TCM of SMs are protected from SIV infection. In the first Aim, we will conduct a systematic comparative analysis of in vivo SIV replication in different CD4+ T cell subsets of SIV-infected SMs and RMs. We will examine different tissues (blood, lymph nodes, mucosal tissues) and CD4+ T cell subsets (Th1, Th2, Th17, and Tregs), and establish correlations with the course of disease progression. In the second Aim, we will study the relationship between SIV replication in central memory CD4+ T cells of LNs and the presence of LN immunopathology, including loss of CD4+ T cells, immune activation, disruption of architecture, fibrosis, and follicular DC virus trapping. In the third Aim, we will assess how SIV replicates in vivo in CD4+ TCM and CD4+ TEM of SMs and RMs by (i) conducting a detailed analysis of the level of integrated proviral DNA, the frequency of SIV-infected cells and the number of RNA copies/cell by limiting dilution analysis, and by (ii) performing sequence analysis of the virus. In the fourth Aim, we will assess the intrinsic susceptibility to SIV infection by CD4+ TCM and CD4+ TEM of uninfected SMs and RMs by conducting experiments of in vitro infection, in which we will seek to identify what stage(s) of virus replication are blocked in CD4+ TCM of SMs. As part of this Aim, we will also study the expression of host restriction factors (i.e., TRIM-5a, APOBECs, and Tetherin) as well as the global transcriptional profile in CD4+ TCM and CD4+ TEM of SMs and RMs. We believe that these studies will advance significantly our understanding of how naturally SIV-infected SMs are resistant to AIDS despite high viremia. We envision that answering this question will provide clues to AIDS pathogenesis in humans that will have ultimately an impact on the prevention and treatment of HIV infection.

Public Health Relevance

Despite a huge effort by the scientific community, there is still neither a cure nor an effective vaccine for AIDS. A major obstacle to achieve these goals is our incomplete understanding of how infection with the human immunodeficiency virus (HIV) causes AIDS. In previous work, others and we have shown that certain African monkeys, such as sooty mangabeys, do not progress to AIDS despite being infected with a virus, the Simian Immunodeficiency Virus (SIV) that is closely related to HIV. The proposed studies are aimed at understanding why the sooty mangabeys are able to remain healthy when infected with SIV. We believe that these studies will improve our comprehension of AIDS pathogenesis in humans and that this knowledge will ultimately translate in better prevention and therapies for the infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI066998-09
Application #
8233311
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2005-09-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$703,587
Indirect Cost
$265,769
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
McGary, Colleen S; Silvestri, Guido; Paiardini, Mirko (2014) Animal models for viral infection and cell exhaustion. Curr Opin HIV AIDS 9:492-9
McGary, Colleen S; Cervasi, Barbara; Chahroudi, Ann et al. (2014) Increased stability and limited proliferation of CD4+ central memory T cells differentiate nonprogressive simian immunodeficiency virus (SIV) infection of sooty mangabeys from progressive SIV infection of rhesus macaques. J Virol 88:4533-42
Cartwright, Emily K; McGary, Colleen S; Cervasi, Barbara et al. (2014) Divergent CD4+ T memory stem cell dynamics in pathogenic and nonpathogenic simian immunodeficiency virus infections. J Immunol 192:4666-73
Chahroudi, Ann; Cartwright, Emily; Lee, S Thera et al. (2014) Target cell availability, rather than breast milk factors, dictates mother-to-infant transmission of SIV in sooty mangabeys and rhesus macaques. PLoS Pathog 10:e1003958
Letko, Michael; Silvestri, Guido; Hahn, Beatrice H et al. (2013) Vif proteins from diverse primate lentiviral lineages use the same binding site in APOBEC3G. J Virol 87:11861-71
Francella, Nicholas; Gwyn, Sarah E; Yi, Yanjie et al. (2013) CD4+ T cells support production of simian immunodeficiency virus Env antibodies that enforce CD4-dependent entry and shape tropism in vivo. J Virol 87:9719-32
Bosinger, Steven E; Johnson, Zachary P; Folkner, Kathryn A et al. (2013) Intact type I Interferon production and IRF7 function in sooty mangabeys. PLoS Pathog 9:e1003597
Evans, David T; Silvestri, Guido (2013) Nonhuman primate models in AIDS research. Curr Opin HIV AIDS 8:255-61
Elliott, Sarah T C; Riddick, Nadeene E; Francella, Nicholas et al. (2012) Cloning and analysis of sooty mangabey alternative coreceptors that support simian immunodeficiency virus SIVsmm entry independently of CCR5. J Virol 86:898-908
Vanderford, Thomas H; Slichter, Chloe; Rogers, Kenneth A et al. (2012) Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood 119:5750-7

Showing the most recent 10 out of 13 publications