[Show abstract][Hide abstract] ABSTRACT: Measures to prevent sexual mucosal transmission are critically needed, particularly to prevent transmission to young women at high risk in the microepidemics in South Africa that disproportionally contribute to the continued pandemic. To that end, microbicides containing anti-retroviral (ARV) agents have been shown to prevent transmission, but with efficacy limited both by adherence and pre-existing innate immune and inflammatory conditions in the female reproductive tract (FRT). Glycerol monolaurate (GML) has been proposed as a microbicide component to enhance efficacy by blocking these transmission-facilitating innate immune response to vaginal exposure. We show here in an especially rigorous test of protection in the SIV-rhesus macaque model of HIV-1 transmission to women, that GML used daily and before vaginal challenge protects against repeat high doses of SIV by criteria that include virological and immunological assays to detect occult infection. We also provide evidence for indirect mechanisms of action in GML-mediated protection. Developing a sustained formulation for GML delivery could contribute an independent, complementary protective component to an ARV-containing microbicide.
PLoS ONE 06/2015; 10(6):e0129465. DOI:10.1371/journal.pone.0129465 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most animal studies using passive administration of HIV broadly neutralizing monoclonal antibodies (bnMAbs) have associated protection against high-dose mucosal viral challenge with relatively high serum concentrations of antibody. We recently identified several bnMAbs remarkable for their in vitro potency against HIV. Of these bnMAbs, PGT121 is one of the most broad and potent antibodies isolated to date and shows 10- to 100-fold higher neutralizing activity than previously characterized bnMAbs. To evaluate the protective potency of PGT121 in vivo, we performed a protection study in rhesus macaques. Animals were i.v. administered 5 mg/kg, 1 mg/kg, or 0.2 mg/kg PGT121 24 h before being vaginally challenged with a single high dose of chimeric simian-human immunodeficiency virus (SHIV)(SF162P3). Sterilizing immunity was achieved in all animals administered 5 mg/kg and 1 mg/kg and three of five animals administered 0.2 mg/kg PGT121, with corresponding average antibody serum concentrations of 95 µg/mL, 15 µg/mL, and 1.8 µg/mL, respectively. The results suggest that a protective serum concentration for PGT121 is in the single-digit µg/mL for SHIV(SF162P3), showing that PGT121 can mediate sterilizing immunity at serum concentrations that are significantly lower than those observed in previous studies and that may be achievable through vaccination with the development of a suitable immunogen.
Proceedings of the National Academy of Sciences 10/2012; 109(46). DOI:10.1073/pnas.1214785109 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Deciphering the complex interactions between human and simian immunodeficiency viruses (HIV/SIV) and their host cells is crucial to the development of improved therapies and vaccines. Investigating these relationships has been complicated by the inability to directly analyze infected cells among freshly isolated peripheral blood lymphocytes. Here, we describe a method to detect cells productively infected with SIVmac239 ex vivo from the blood or lymph nodes by flow cytometry. Using this method, we show a close correlation between the frequency of productively infected cells in both sample type and the plasma viral load. We define that the minimum threshold for detecting productively infected cells in lymph nodes by flow cytometry requires a plasma virus concentration of ∼2.5 × 10(4) vRNA copy Equivalents (Eq)/ml. Conversely, an approximately 2 logs higher plasma viral load is needed to detect productively infected cells in the peripheral blood. This novel protocol provides a direct analytical tool to assess interactions between SIV and host cells, which is of key importance to investigators in AIDS research.
Cytometry Part A 11/2010; 77(11):1059-66. DOI:10.1002/cyto.a.20960 · 2.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human and simian immunodeficiency viruses (HIV and SIV) downregulate major histocompatibility complex class I (MHC-I) molecules
from the surface of infected cells. Although this activity is conserved across viral isolates, its importance in AIDS pathogenesis
is not clear. We therefore developed an assay to detect the level of MHC-I expression of SIV-infected cells directly ex vivo. Here we show that the extent of MHC-I downregulation is greatest in SIVmac239-infected macaques that never effectively control
virus replication. Our results suggest that a high level of MHC-I downregulation is a hallmark of fast disease progression
in SIV infection.
Journal of Virology 03/2010; 84(10):5443-7. DOI:10.1128/JVI.02452-09 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The membrane-proximal external region (MPER) of HIV-1, located at the C terminus of the gp41 ectodomain, is conserved and
crucial for viral fusion. Three broadly neutralizing monoclonal antibodies (bnMAbs), 2F5, 4E10, and Z13e1, are directed against
linear epitopes mapped to the MPER, making this conserved region an important potential vaccine target. However, no MPER antibodies
have been definitively shown to provide protection against HIV challenge. Here, we show that both MAbs 2F5 and 4E10 can provide
complete protection against mucosal simian-human immunodeficiency virus (SHIV) challenge in macaques. MAb 2F5 or 4E10 was
administered intravenously at 50 mg/kg to groups of six male Indian rhesus macaques 1 day prior to and again 1 day following
intrarectal challenge with SHIVBa-L. In both groups, five out of six animals showed complete protection and sterilizing immunity, while for one animal in each
group a low level of viral replication following challenge could not be ruled out. The study confirms the protective potential
of 2F5 and 4E10 and supports emphasis on HIV immunogen design based on the MPER region of gp41.
Journal of Virology 11/2009; 84(3):1302-13. DOI:10.1128/JVI.01272-09 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Understanding the correlates of immune protection against human immunodeficiency virus and simian immunodeficiency virus (SIV) will require defining the entire cellular immune response against the viruses. Here, we define two novel translation products from the SIV env mRNA that are targeted by the T-cell response in SIV-infected rhesus macaques. The shorter product is a subset of the larger product, which contains both the first exon of the Rev protein and a translated portion of the rev intron. Our data suggest that the translation of viral alternate reading frames may be an important source of T-cell epitopes, including epitopes normally derived from functional proteins.
Journal of Virology 08/2009; 83(19):10280-5. DOI:10.1128/JVI.00138-09 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: “Elite controllers” are individuals that durably control human immunodeficiency virus or simian immunodeficiency virus replication
without therapeutic intervention. The study of these rare individuals may facilitate the definition of a successful immune
response to immunodeficiency viruses. Here we describe six Indian-origin rhesus macaques that have controlled replication
of the pathogenic virus SIVmac239 for 1 to 5 years. To determine which lymphocyte populations were responsible for this control,
we transiently depleted the animals’ CD8+ cells in vivo. This treatment resulted in 100- to 10,000-fold increases in viremia. When the CD8+ cells returned, control was reestablished and the levels of small subsets of previously subdominant CD8+ T cells expanded up to 2,500-fold above predepletion levels. This wave of CD8+ T cells was accompanied by robust Gag-specific CD4 responses. In contrast, CD8+ NK cell frequencies changed no more than threefold. Together, our data suggest that CD8+ T cells targeting a small number of epitopes, along with broad CD4+ T-cell responses, can successfully control the replication of the AIDS virus. It is likely that subdominant CD8+ T-cell populations play a key role in maintaining this control.
Journal of Virology 05/2007; 81(7):3465-76. DOI:10.1128/JVI.02392-06 · 4.44 Impact Factor