Target Cell Availability, Rather than Breast Milk Factors, Dictates Mother-to-Infant Transmission of SIV in Sooty Mangabeys and Rhesus Macaques

Chahroudi, Ann; Cartwright, Emily K.; Lee, S. Thera; Mavigner, Maud; Carnathan, Diane G.; Lawson, Benton; Carnathan, Paul M.; Hashempoor, Tayebeh; Murphy, Megan K.; Meeker, Tracy; Ehnert, Stephanie; Souder, Christopher; Else, James G.; Cohen, Joyce; Collman, Ronald G.; Vanderford, Thomas H.; Permar, Sallie R.; Derdeyn, Cynthia A.; Villinger, François; Silvestri, Guido

doi:10.1371/journal.ppat.1003958

Cited by 42 publications

(42 citation statements)

References 44 publications

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“…This could result from the generation and homing of vaccine-elicited CD4+ T cells to the portal of entry, which in turn mitigates the beneficial effects of the vaccine-elicited humoral immune response (38-40). Indeed, the efficiency of horizontal and vertical SIV transmission in NHP hosts in the absence of vaccination is linked to the availability of susceptible target cells in the mucosa (41)(42)(43). Furthermore, there is strong evidence that genital inflammation reduces the stringency of HIV-1 transmission (25,44,45) and increased target cell availability increases the risk of HIV-1 superinfection (46).…”

Section: Discussionmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

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Section: Discussionmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, we have previously described strong autologous virus neutralization responses in the breast milk of chronically SIV-infected AGMs (50, 51), a response that could impede the initiation of infection in the infant gastrointestinal tract by autologous maternal virus variants. However, evidence in SMs suggests that the lack of vertical SIV transmission in this natural host species stems from low CD4 ϩ CCR5 ϩ target cell availability in the infant (69). Identification of the immunodominant SIV gp120 and gp41 epitopes and how they relate to the functional roles of the rapidly elicited and gp120-focused acute antibody responses in natural SIV hosts may help to inform vaccine strategies for a similar rapid development of HIV-1 neutralizing antibody responses.…”

Section: Discussionmentioning

confidence: 99%

Rapid Development of gp120-Focused Neutralizing B Cell Responses during Acute Simian Immunodeficiency Virus Infection of African Green Monkeys

Amos

Himes

Armand

et al. 2015

J Virol

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The initial phases of acute human immunodeficiency virus type 1 (HIV-1) infection may be critical for development of effective envelope (Env)-specific antibodies capable of impeding the establishment of the latent pool of HIV-1-infected CD4؉ T cells, preventing virus-induced immune hyperactivation to limit disease progression and blocking vertical virus transmission. However, the initial systemic HIV-1 Env-specific antibody response targets gp41 epitopes and fails to control acute-phase viremia. Africanorigin, natural simian immunodeficiency virus (SIV) hosts do not typically progress to AIDS and rarely postnatally transmit virus to their infants, despite high milk viral loads. Conversely, SIV-infected rhesus macaques (RMs), Asian-origin nonnatural SIV hosts, sustain pathogenic SIV infections and exhibit higher rates of postnatal virus transmission. In this study, of acute SIV infection, we compared the initial systemic Env-specific B cell responses of AGMs and RMs in order to probe potential factors influencing the lack of disease progression observed in AGMs. AGMs developed higher-magnitude plasma gp120-specific IgA and IgG responses than RMs, whereas RMs developed more robust gp140-directed IgG responses. These gp120-focused antibody responses were accompanied by rapid autologous neutralizing responses during acute SIV infection in AGMs compared to RMs. Moreover, acute SIV infection elicited a higher number of circulating Env-specific memory B cells in peripheral blood of AGMs than in the blood of RMs. These findings indicate that AGMs have initial systemic Env-specific B cell responses to SIV infection distinct from those of a nonnatural SIV host, resulting in more functional SIV-specific humoral responses, which may be involved in impairing pathogenic disease progression and minimizing postnatal transmission. A major goal for a safe and effective human immunodeficiency virus type 1 (HIV-1) vaccine is to induce broadly neutralizing antibodies (bnAbs) capable of protecting against acquisition of HIV-1 strains across all genetic subtypes (1). Moreover, treatment of chronically simian-human immunodeficiency virus (SHIV)-infected monkeys and HIV-1-infected humanized mice with bnAbs isolated from HIV-1-infected individuals has resulted in reduced size of the latent virus reservoir and control of systemic viremia (2, 3). However, to date, there is no immunogen formulation that successfully induces bnAbs in humans. Broad neutralizing responses typically arise naturally after many years of HIV-1 infection and do not occur in all people (4-8). In addition, the appearance of autologous neutralizing antibody responses in infected individuals against the transmitted/founder (T/F) HIV-1 strain(s) is also delayed, emerging months after primary HIV-1 infection (9-12). Notably, autologous and broadly neutralizing antibody responses are predominantly targeted against envelope (Env) gp120 epitopes as opposed to gp41 epitopes, including the

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“…DNA was extracted from sorted peripheral and lymph node CD4 ϩ T cells and CD4 ϩ T-cell memory subsets using the Blood DNA minikit (Qiagen). Quantifi-cation of SIV mac gag DNA was performed as previously described on the extracted cell-associated DNA by quantitative PCR using the 5= nuclease (TaqMan) assay with an ABI7500 system (PerkinElmer Life Sciences) (19). The sequence of the forward primer for SIV mac gag was 5=-GCAGA GGAGGAAATTACCCAGTAC-3=; the reverse primer sequence was 5=-C AATTTTACCCAGGCATTTAATGTT-3=; and the probe sequence was 5=-6-FAM-TGTCCACCTGCCATTAAGCCCGA-TAMRA-3=, where 6-FAM is 6-carboxyfluorescein.…”

Section: Methodsmentioning

confidence: 99%

Initiation of Antiretroviral Therapy Restores CD4 ⁺ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

Cartwright

Palesch

Mavigner

et al. 2016

J Virol

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Treatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4؉ T memory stem cells (T SCM ) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4؉ T SCM are preserved in number but show (i) a decrease in the frequency of CCR5 ؉ cells, (ii) an expansion of the fraction of proliferating Ki-67 ؉ cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4؉ T SCM homeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4 ؉ CCR5 ؉ T SCM both in blood and in lymph nodes and a reduction in the fraction of proliferating CD4؉ Ki-67 ؉ T SCM in blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4؉ transitional memory (T TM ) and effector memory (T EM ) T cells declined ϳ100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4؉ T SCM and central memory T cells (T CM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4 ؉ T SCM homeostasis, and the observed stable level of virus in T SCM supports the hypothesis that these cells are a critical contributor to SIV persistence. IMPORTANCE Understanding the roles of various CD4؉ T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (T SCM ) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (T CM and T TM , respectively). CD4 ؉ T SCM are disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4 ؉ T SCM homeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as T TM and effector memory (T EM ). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4 ؉ T SCM during suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir. Infection with pathogenic lentiviruses such as human and simian immunodeficiency viruses (HIV and SIV, respectively) significantly perturbs the homeostasis of the CD4 ϩ T cell compartment through preferential infection and depletion of memory CD4 ϩ T cells, which is the hallmark of progression to AIDS. While the availability of antiretroviral therapy (ART) has significantly reduced the mortality and ...

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Target Cell Availability, Rather than Breast Milk Factors, Dictates Mother-to-Infant Transmission of SIV in Sooty Mangabeys and Rhesus Macaques

Cited by 42 publications

References 44 publications

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Rapid Development of gp120-Focused Neutralizing B Cell Responses during Acute Simian Immunodeficiency Virus Infection of African Green Monkeys

Initiation of Antiretroviral Therapy Restores CD4 ⁺ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

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Target Cell Availability, Rather than Breast Milk Factors, Dictates Mother-to-Infant Transmission of SIV in Sooty Mangabeys and Rhesus Macaques

Cited by 42 publications

References 44 publications

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Rapid Development of gp120-Focused Neutralizing B Cell Responses during Acute Simian Immunodeficiency Virus Infection of African Green Monkeys

Initiation of Antiretroviral Therapy Restores CD4 + T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

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Initiation of Antiretroviral Therapy Restores CD4 ⁺ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques