Genetically diverse subtypes and recombinant forms of HIV-1 circulate in different regions of the globe and are the basis of the current AIDS pandemic. The biological consequences of this viral diversity are poorly understood and pose s substantial challenge for vaccination. In HIV-1 infected patients, the immune system makes neutralizing antibodies against the HIV-1 envelope glycoproteins, but these proteins are highly variable in sequence, especially between subtypes, and they utilize sophisticated mechanisms to avoid immune recognition. The study of virus neutralization and escape in patients that harbor globally prevalent genetic subtypes of HIV-1 is therefore of substantial interest. The goal of the proposed studies is to better understand how antibodies neutralize subtype C HIV-1, which predominates in sub-Saharan Africa, and to determine how the virus escapes from immune recognition. The studies will be performed using viral envelope clones derived from longitudinally collected material (blood cell DNA and plasma) from recently infected, treatment-naive subjects in a discordant couple cohort in Zambia, where subtype C HIV-1 predominates. The ability of antibodies in patient plasma to neutralize autologous viral envelope clones will be evaluated for a panel of 15 seroconvertors using a single round infection assay, and molecular approaches will be used to isolate patient-derived antibodies, identify neutralization targets, and reconstruct pathways of viral escape. Mutational patterns that occur in a helical domain of the envelope and are peripherally associated with neutralization escape will also be investigated. The hypotheses are that (i) the major escape pathways operative in early subtype C infection differ from those reported to dominate in subtype B infection, (ii) these escape pathways carry a fitness cost and are dependent on ancillary changes in the a2 helix, and (iii) B cell responses in subtype C infection target strain-specific and shared regions of Env that are distinct from those defined for subtype B infection.

Public Health Relevance

Neutralizing antibodies in HIV-1 infection are directed against the envelope (Env) glycoproteins gp120 and gp41. However, HIV-1 Env utilizes highly effective, but poorly defined, overlapping mechanisms to evade antibody-mediated neutralization. Our lack of information about the B cell responses, targets of autologous neutralization, and mechanisms of viral escape in subtype C infection represents a significant gap in our understanding of the most predominant HIV-1 variants worldwide. The goal of these studies is therefore to identify B cell targets and define mechanisms of virus neutralization and escape in newly infected subtype C patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058706-10
Application #
8242820
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2004-03-01
Project End
2013-04-14
Budget Start
2012-03-01
Budget End
2013-04-14
Support Year
10
Fiscal Year
2012
Total Cost
$431,244
Indirect Cost
$186,219
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Smith, S Abigail; Kilgore, Katie M; Kasturi, Sudhir Pai et al. (2016) Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques. J Virol 90:1880-7
Gu, Linlin; Krendelchtchikova, Valentina; Krendelchtchikov, Alexandre et al. (2016) Adenoviral vectors elicit humoral immunity against variable loop 2 of clade C HIV-1 gp120 via "Antigen Capsid-Incorporation" strategy. Virology 487:75-84
Cartwright, Emily K; Spicer, Lori; Smith, S Abigail et al. (2016) CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity 45:656-68
Elliott, Sarah T C; Wetzel, Katherine S; Francella, Nicholas et al. (2015) Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV. J Virol 89:9252-61
Yue, Ling; Pfafferott, Katja J; Baalwa, Joshua et al. (2015) Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients. PLoS Pathog 11:e1004565
Peters, Paul J; Gonzalez-Perez, Maria Paz; Musich, Thomas et al. (2015) Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes. Retrovirology 12:48
Kilgore, Katie M; Murphy, Megan K; Burton, Samantha L et al. (2015) Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope. J Virol 89:8130-51
Smith, S Abigail; Derdeyn, Cynthia A (2015) A pathway to HIV-1 neutralization breadth. Nat Med 21:1246-7
Musich, Thomas; O'Connell, Olivia; Gonzalez-Perez, Maria Paz et al. (2015) HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages. Retrovirology 12:25
Burton, Samantha L; Kilgore, Katie M; Smith, S Abigail et al. (2015) Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses. Proc Natl Acad Sci U S A 112:10780-5

Showing the most recent 10 out of 40 publications