Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

Amos, Joshua D.; Wilks, Andrew B.; Fouda, Genevieve G.; Smith, Shannon D.; Colvin, Lisa; Mahlokozera, Tatenda; Ho, Carrie; Beck, Krista; Overman, R. Glenn; DeMarco, C. Todd; Hodge, Terry L.; LaBranche, Celia C.; Montefiori, David C.; Denny, Thomas N.; Liao, Hua‐Xin; Tomaras, Georgia D.; Moody, M. Anthony; Permar, Sallie R.

doi:10.1128/jvi.01887-13

Cited by 14 publications

(26 citation statements)

References 69 publications

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“…The rapid development of effective autologous neutralizing responses further suggests the importance of this early gp120-specific response. The high-magnitude acute gp120-specific antibody responses in AGMs are also consistent with our previous observations of gp120-dominant IgA and IgG binding responses in the milk and plasma of chronically SIV-infected AGMs (51). While IgG responses against the Env variable loops were detected in AGMs following acute SIV infection, the epitope specificity of the acute anti-gp120 IgA response is unknown, as we were not able to detect IgA responses against the well-established primary IgG binding sites on HIV/SIV Env, including the V1/V2 loop, the V3 loop, and the CD4bs, during acute infection of AGMs (62).…”

Section: Discussionsupporting

confidence: 77%

“…We previously identified limited B cell dysfunction, lack of hypergammaglobulinemia, and the presence of strong gp120-focused and autologous virus-neutral- izing antibody responses in the milk and plasma of chronically SIV-infected AGMs compared to that of nonnatural SIV hosts, RMs (50,51). In the present study, we report the earlier development of high-magnitude and more functional systemic gp120-specific antibody responses and Env-specific memory B cell population evolution during acute SIV infection in AGMs compared to that in RMs, implicating differences in the preexisting or acute antibody response to SIV as potential contributors to the distinct virus-specific B cell responses in these natural SIV host species.…”

Section: Discussionmentioning

confidence: 99%

“…Six female AGMs and four female RMs were hormonally induced into lactation, followed by intravenous inoculation with SIVsab92018ivTF and SIVmac251, respectively, as described previously (51,52). Blood was collected prior to infection and once per week at 1 to 6, 15 to 26, and 52 to 64 weeks postinfection.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative reverse transcriptase PCR (RT-PCR) was performed to determine the SIVsab92018ivTF and SIVmac251 plasma RNA loads, as described previously (50,51).…”

Section: Methodsmentioning

confidence: 99%

“…However, strain-specific autologous neutralizing responses, some with high potency, have been characterized in the plasma and breast milk of SIV-infected AGMs (49,50). Moreover, we previously described a lack of hypergammaglobulinemia, in addition to robust gp120 binding and strong autologous virus-neutralizing antibody responses, in the plasma and milk of chronically SIV-infected AGMs (50,51), factors that indicate a lack of B cell dysfunction that may contribute to the limited disease pathogenesis and rarity of postnatal transmission in this natural SIV host species. In this study, we compared the kinetics of the initial systemic SIV Env-specific antibody responses and B cell subpopulations in AGMs to those of rhesus macaques (RMs), a nonnatural SIV host species.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Quantitative reverse transcriptase PCR (RT-PCR) was performed to determine the SIVsab92018ivTF and SIVmac251 plasma RNA loads, as described previously (50,51).…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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