Gag-Specific Cellular Immunity Determines
            <i>In Vitro</i>
            Viral Inhibition and
            <i>In Vivo</i>
            Virologic Control following Simian Immunodeficiency Virus Challenges of Vaccinated Rhesus Monkeys

Stephenson, Kathryn E.; Li, Hualin; Walker, Bruce D.; Michael, Nelson L.; Barouch, Dan H.

doi:10.1128/jvi.00996-12

Cited by 38 publications

(24 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the modest virologic control likely reflected Env-specific immune responses, although the magnitude and breadth of Env-specific T lymphocyte responses were not clearly correlated with virologic control (Supplementary Table S2). This is consistent with our previous observations that virologic control following challenge is primarily mediated by Gag-specific cellular immune responses (Stephenson et al, 2012a), and thus it is not surprising that the observed virologic control was only modest in this study. In contrast, similar Ad/MVA and Ad/Ad vector regimens expressing SIVsmE543 antigens afforded >2 log reductions of setpoint viral loads following heterologous SIVmac251 challenges (Barouch et al, 2012).…”

Section: Resultssupporting

confidence: 94%

Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys

Barouch

Stephenson

Borducchi

et al. 2013

Cell

315

303

View full text Add to dashboard Cite

SUMMARY The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of global HIV-1 vaccine antigens has not previously been evaluated. Here we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection was correlated with vaccine-elicited binding, neutralizing, and functional non-neutralizing antibodies. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy towards the development of a global HIV-1 vaccine. Moreover, our findings suggest that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses.

show abstract

Section: Resultssupporting

confidence: 94%

Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys

Barouch

Stephenson

Borducchi

et al. 2013

Cell

315

303

View full text Add to dashboard Cite

show abstract

“…A significant inhibition of HIV-1 infectivity of PBMCs was found ex vivo postimmunization compared with that preimmunization. Although the infection was assayed ex vivo, there is evidence from studies in rhesus macaques that ex vivo viral inhi- bition is consistent with in vivo viral control following viral challenge of the vaccinated animals (31). HIV tropism is largely generated by coreceptor selection, but initial transmission is commonly by the R5 strain of HIV-1, which utilizes the CCR5 coreceptor (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Effect of Vaginal Immunization with HIVgp140 and HSP70 on HIV-1 Replication and Innate and T Cell Adaptive Immunity in Women

Lewis

Wang

Huo

et al. 2014

J Virol

View full text Add to dashboard Cite

The international effort to prevent HIV-1 infection by vaccination has failed to develop an effective vaccine. The aim of this vaccine trial in women was to administer by the vaginal mucosal route a vaccine consisting of HIV-1 gp140 linked to the chaperone 70-kDa heat shock protein (HSP70). The primary objective was to determine the safety of the vaccine. The secondary objective was to examine HIV-1 infectivity ex vivo and innate and adaptive immunity to HIV-1. Protocol-defined female volunteers were recruited. HIV-1 CN54gp140 linked to HSP70 was administered by the vaginal route. Significant adverse reactions were not detected. HIV-1 was significantly inhibited ex vivo in postimmunization CD4؉ T cells compared with preimmunization CD4 ؉ T cells. The innate antiviral restrictive factor APOBEC3G was significantly upregulated, as were CC chemokines which induce downregulation of CCR5 in CD4 ؉ T cells. Indeed, a significant inverse correlation between the proportion of CCR5 ؉ T cells and the concentration of CCL-3 or CCL-5 was found. Importantly, the upregulation of APOBEC3G showed a significant inverse correlation, whereas CCR5 exhibited a trend to correlate with inhibition of HIV-1 infection (r ‫؍‬ 0.51). Furthermore, specific CD4 ؉ and CD8 ؉ T cells showed HIVgp140-and HSP70-specific proliferation. A strong inverse correlation between the proportion of CC chemokine-modulated CCR5-expressing CD4 ؉ T cells and the stimulation of CD4 ؉ or CD8 ؉ T cell proliferation by HIVgp140 was found, demonstrating a significant interaction between innate and adaptive immunity. This is the first clinical trial of vaginal immunization in women using only HIVgp140 and HSP70 administered by the mucosal route (3 times) in which a dual innate protective mechanism was induced and enhanced by significant adaptive CD4 ؉ and CD8 ؉ T cell proliferative responses.

show abstract

“…Recently we have evaluated an Ad26 vector-based vaccine for HIV-1 in clinical trials (7, 8), and preclinical studies with Ad26-based vaccine regimens in non-human primates resulted in partial protection against acquisition of infection as well as virologic control following SIV mac251 challenges (9–11). Virologic control correlated with vaccine-elicited SIV-specific CD8 + T cell responses (9–12). However, relatively little is known about the CD4 + T cell requirement to generate CD8 + T cell memory responses following vaccination.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Requirement for CD4+ T Cell Help for Adenovirus Vector–Elicited CD8+ T Cell Responses

Provine

Larocca

Penaloza-MacMaster

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Despite the widespread use of replication-incompetent recombinant adenovirus (Ad) vectors as candidate vaccine platforms, the mechanism by which these vectors elicit CD8+ T cell responses remains poorly understood. Our data demonstrate that induction and maintenance of CD8+ T cell responses by Ad vector immunization is longitudinally dependent on CD4+ T cell help for a prolonged period of time. Depletion of CD4+ T cells in wild type mice within the first eight days following Ad immunization resulted in dramatically reduced induction of antigen-specific CD8+ T cells, decreased T-bet and Eomesodermin expression, impaired KLRG1+ effector differentiation, and atypical expression of the memory markers CD127, CD27, and CD62L. Moreover, these CD8+ T cells failed to protect against a lethal recombinant Listeria monocytogenes challenge. Depletion of CD4+ T cells between week 1 and week 4 following immunization resulted in increased contraction of memory CD8+ T cells. These data demonstrate a prolonged temporal requirement for CD4+ T cell help for vaccine-elicited CD8+ T cell responses in mice. These findings have important implications in the design of vaccines aimed at eliciting CD8+ T cell responses and may provide insight into the impaired immunogenicity of vaccines in the context of AIDS and other CD4+ T cell immune deficiencies.

show abstract

Gag-Specific Cellular Immunity Determines In Vitro Viral Inhibition and In Vivo Virologic Control following Simian Immunodeficiency Virus Challenges of Vaccinated Rhesus Monkeys

Cited by 38 publications

References 29 publications

Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys

Protective Efficacy of a Global HIV-1 Mosaic Vaccine against Heterologous SHIV Challenges in Rhesus Monkeys

Effect of Vaginal Immunization with HIVgp140 and HSP70 on HIV-1 Replication and Innate and T Cell Adaptive Immunity in Women

Longitudinal Requirement for CD4+ T Cell Help for Adenovirus Vector–Elicited CD8+ T Cell Responses

Contact Info

Product

Resources

About