An adenovirus-simian immunodeficiency virus env vaccine elicits humoral, cellular, and mucosal immune responses in rhesus macaques and decreases viral burden following vaginal challenge.

ABSTRACT In rhesus macaques, classic systemic infection, characterized by persistent viremia and seroconversion, occurred after multiple low-dose (103 50% tissue culture infective doses) intravaginal (IVAG) inoculations with simian immunodeficiency virus (SIV) strain SIVmac251. Monkeys developed classic SIV infections after a variable number of low-dose IVAG exposures to SIVmac251. Once established, the systemic infection was identical to SIV infection following high-dose IVAG SIV inoculation. However, occult systemic infection characterized by transient cell-associated or cell-free viremia consistently occurred early in the series of multiple vaginal SIV exposures. Further, antiviral cellular immune responses were present prior to the establishment of a classic systemic infection in the low-dose vaginal SIV transmission model.

Download Full-text

Recombinant Herpesvirus Vectors: Durable Immune Responses and

Journal of Virology ◽

10.1128/jvi.00330-21 ◽

2021 ◽

Author(s):

Isabelle M. Castro ◽

Michael J. Ricciardi ◽

Lucas Gonzalez-Nieto ◽

Eva G. Rakasz ◽

Jeffrey D. Lifson ◽

...

Keyword(s):

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Vaccine Development ◽

Rhesus Macaques ◽

Antigen Expression ◽

Challenge Virus ◽

Immunodeficiency Virus ◽

Herpesvirus Vector ◽

Gamma Herpesvirus

A prophylactic vaccine that confers durable protection against human immunodeficiency virus (HIV) would provide a valuable tool to prevent new HIV/AIDS cases. As herpesviruses establish lifelong infections that remain largely subclinical, the use of persistent herpesvirus vectors to deliver HIV antigens may facilitate the induction of long-term anti-HIV immunity. We previously developed recombinant (r) forms of the gamma-herpesvirus rhesus monkey rhadinovirus (rRRV) expressing a replication-incompetent, near-full-length simian immunodeficiency virus (SIVnfl) genome. We recently showed that 8/16 rhesus macaques (RMs) vaccinated with a rDNA/rRRV-SIVnfl regimen were significantly protected against intrarectal (IR) challenge with SIVmac239. Here we investigated the longevity of this vaccine-mediated protection. Despite receiving no additional booster immunizations, the protected rDNA/rRRV-SIVnfl vaccinees maintained detectable cellular and humoral anti-SIV immune responses for more than 1.5 years after the rRRV boost. To assess if these responses were still protective, the rDNA/rRRV-SIVnfl vaccinees were subjected to a second round of marginal-dose IR SIVmac239 challenges, with eight SIV-naïve RMs serving as concurrent controls. After three SIV exposures, 8/8 control animals became infected, compared to 3/8 vaccinees. This difference in SIV acquisition was statistically significant (P = 0.0035). The three vaccinated monkeys that became infected exhibited significantly lower viral loads than those in unvaccinated controls. Collectively, these data illustrate the ability of rDNA/rRRV-SIVnfl vaccination to provide long-term immunity against stringent mucosal challenges with SIVmac239. Future work is needed to identify the critical components of this vaccine-mediated protection and the extent to which it can tolerate sequence mismatches in the challenge virus. IMPORTANCE We report on the long-term follow-up of a group of rhesus macaques (RMs) that received an AIDS vaccine regimen and were subsequently protected against rectal acquisition of simian immunodeficiency virus (SIV) infection. The vaccination regimen employed included a live recombinant herpesvirus vector that establishes persistent infection in RMs. Consistent with the recurrent SIV antigen expression afforded by this herpesvirus vector, vaccinees maintained detectable SIV-specific immune responses for more than 1.5 years after the last vaccination. Importantly, these vaccinated RMs were significantly protected against a second round of rectal SIV exposures performed one year after the first SIV challenge phase. These results are relevant for HIV vaccine development because they show the potential of herpesvirus-based vectors to maintain functional antiretroviral immunity without the need for repeated boosting.

Download Full-text

Improved Protection of Rhesus Macaques against Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge by a Replication-Competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag Recombinant Priming/gp120 Boosting Regimen

Journal of Virology ◽

10.1128/jvi.77.15.8354-8365.2003 ◽

2003 ◽

Vol 77 (15) ◽

pp. 8354-8365 ◽

Cited By ~ 41

Author(s):

Jun Zhao ◽

Joel Pinczewski ◽

Victor R. Gómez-Román ◽

David Venzon ◽

V. S. Kalyanaraman ◽

...

Keyword(s):

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Acute Infection ◽

Neutralizing Antibody ◽

Antibody Activity ◽

Viral Loads ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Cellular Immune

ABSTRACT In this study we investigated the ability of a replication-competent Ad5hr-SIVenv/rev and Ad5hr-SIVgag recombinant priming/gp120 boosting regimen to induce protective immunity in rhesus macaques against pathogenic simian immunodeficiency virusmac251. Immunization of macaques by two sequential administrations of the same recombinants by the same route resulted in boosting and persistence of SIV-specific cellular immune responses for 42 weeks past the initial immunization. Anti-SIV gp120 immunoglobulin G (IgG) and IgA antibodies were induced in secretory fluids, and all macaques exhibited serum neutralizing antibody activity. After intrarectal SIVmac251 challenge, all of the macaques became infected. However, relative protection, as assessed by statistically significant lower SIV viral loads in plasma at both acute infection and set point, was observed in 8 out of 12 immunized non-Mamu-A∗01 animals. Elevated mean cellular immune responses to Gag and Env, neutralizing antibody activity, and IgG and IgA binding antibody levels were observed in the eight protected macaques. Statistically significant correlations with protective outcome were observed for cellular immune responses to SIV Env and Gag and for SIV gp120-specific IgG antibodies in nasal and vaginal fluids. Two macaques that exhibited the greatest and most persistent viremia control also exhibited strong CD8+ T-cell antiviral activity. The results suggest that a spectrum of immune responses may be necessary for adequate control of viral replication and disease progression and highlight a potential role for nonneutralizing antibodies at mucosal sites.

Download Full-text

Vaccine protection from CD4+ T-cell loss caused by simian immunodeficiency virus (SIV) mac251 is afforded by sequential immunization with three unrelated vaccine vectors encoding multiple SIV antigens

Journal of General Virology ◽

10.1099/vir.0.80226-0 ◽

2004 ◽

Vol 85 (10) ◽

pp. 2915-2924 ◽

Cited By ~ 30

Author(s):

Gerrit Koopman ◽

Daniella Mortier ◽

Sam Hofman ◽

Henk Niphuis ◽

Zahra Fagrouch ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Cell Function ◽

Semliki Forest Virus ◽

Rhesus Macaques ◽

Cell Loss ◽

Inverse Association ◽

Immunodeficiency Virus

Candidate human immunodeficiency virus (HIV) vaccine strategies that induce strong cellular immune responses protect rhesus macaques that are infected with recombinant simian/human immunodeficiency virus SHIV89.6p from acute CD4+ T-cell loss and delay progression to AIDS. However, similar strategies have not proven as efficacious in the simian immunodeficiency virus (SIV)mac model of AIDS, an infection that causes a slow, steady loss of CD4+ T-cell function and numbers in rhesus macaques similar to that caused by HIV-1, the principal cause of AIDS in humans. Efforts to increase vaccine efficacy by repeated boosting with the same vector are quickly limited by rising anti-vector immune responses. Here, the sequential use of three different vectors (DNA, Semliki Forest virus and modified vaccinia virus Ankara) encoding the same SIVmac structural and regulatory antigens was investigated and demonstrated to prevent or slow the loss of CD4+ T-cells after mucosal challenge with the highly pathogenic SIVmac251 strain. Of particular interest was an inverse association between the extent of T-helper 2 cytokine responses and steady-state virus load. Although limited in the number of animals, this study provides important proof of the efficacy of the triple-vector vaccine strategy against chronic, progressive CD4+ T-cell loss in the rigorous SIVmac/rhesus macaque model of AIDS.

Download Full-text

Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Vectors Prime for Strong Cellular Responses to Simian Immunodeficiency Virus Gag in Rhesus Macaques

Clinical and Vaccine Immunology ◽

10.1128/cvi.00324-14 ◽

2014 ◽

Vol 21 (10) ◽

pp. 1385-1395 ◽

Cited By ~ 9

Author(s):

Jaimie D. Sixsmith ◽

Michael W. Panas ◽

Sunhee Lee ◽

Geoffrey O. Gillard ◽

KeriAnn White ◽

...

Keyword(s):

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Mycobacterium Bovis ◽

Rhesus Macaques ◽

Vaccine Vector ◽

Effective Vaccine ◽

Bacillus Calmette Guerin ◽

Immunodeficiency Virus ◽

Specific Priming

ABSTRACTLive attenuated nonpathogenicMycobacterium bovisbacillus Calmette-Guérin (BCG) mediates long-lasting immune responses, has been safely administered as a tuberculosis vaccine to billions of humans, and is affordable to produce as a vaccine vector. These characteristics make it very attractive as a human immunodeficiency virus (HIV) vaccine vector candidate. Here, we assessed the immunogenicity of recombinant BCG (rBCG) constructs with different simian immunodeficiency virus (SIV)gagexpression cassettes as priming agents followed by a recombinant replication-incompetent New York vaccinia virus (NYVAC) boost in rhesus macaques. Unmutated rBCG constructs were used in comparison to mutants with gene deletions identified in anin vitroscreen for augmented immunogenicity. We demonstrated that BCG-SIVgagis able to elicit robust transgene-specific priming responses, resulting in strong SIV epitope-specific cellular immune responses. While enhanced immunogenicity was sustained at moderate levels for >1 year following the heterologous boost vaccination, we were unable to demonstrate a protective effect after repeated rectal mucosal challenges with pathogenic SIVmac251. Our findings highlight the potential for rBCG vaccines to stimulate effective cross-priming and enhanced major histocompatibility complex class I presentation, suggesting that combining this approach with other immunogens may contribute to the development of effective vaccine regimens against HIV.

Download Full-text

Factors Associated with Slow Disease Progression in Macaques Immunized with an Adenovirus-Simian Immunodeficiency Virus (SIV) Envelope Priming-gp120 Boosting Regimen and Challenged Vaginally with SIVmac251

Journal of Virology ◽

10.1128/jvi.73.9.7430-7440.1999 ◽

1999 ◽

Vol 73 (9) ◽

pp. 7430-7440 ◽

Cited By ~ 46

Author(s):

Suzan L. Buge ◽

Lalita Murty ◽

Kamalpreet Arora ◽

V. S. Kalyanaraman ◽

Phillip D. Markham ◽

...

Keyword(s):

Immune Responses ◽

Disease Progression ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Viral Envelope ◽

Virus Envelope ◽

Partial Protection ◽

Vaccine Regimen ◽

Cd4 Counts ◽

Immunodeficiency Virus

ABSTRACT Rhesus macaques were immunized with a combination vaccine regimen consisting of adenovirus type 5 host range mutant-simian immunodeficiency virus envelope (Ad5hr-SIVenv) recombinant priming and boosting with native SIV gp120. Upon intravaginal challenge with SIVmac251, both persistently and transiently viremic animals were observed (S. L. Buge, E. Richardson, S. Alipanah, P. Markham, S. Cheng, N. Kalyan, C. J. Miller, M. Lubeck, S. Udem, J. Eldridge, and M. Robert-Guroff, J. Virol. 71:8531–8541, 1997). Long-term follow-up of the persistently viremic immunized macaques, which displayed significantly reduced viral burdens during the first 18 weeks postchallenge compared to controls, has now shown that one of four became a slow progressor, clearing virus from plasma and remaining asymptomatic with stable CD4 counts for 134 weeks postchallenge. Reboosting of the transiently viremic macaques did not reactivate latent virus. Rechallenge with two sequential SIVmac251 intravaginal exposures again resulted in partial protection of one of two immunized macaques, manifested by viral clearance and stable CD4 counts. No single immune parameter was associated with partial protection. Development of a strong antibody response capable of neutralizing a primary SIVmac251 isolate together with SIV-specific cytotoxic T lymphocytes were implicated, while CD8+ T-cell antiviral activity and mucosal immune responses were not associated with delayed disease progression. Our data show that even a third immunization with the same Ad5hr-SIVenv recombinant can elicit significant immune responses to the inserted gene product, suggesting that preexisting Ad antibodies may not preclude effective immunization. Further, the partial protection against a virulent, pathogenic SIV challenge observed in two of six macaques immunized with a vaccine regimen based solely on the viral envelope indicates that this vectored-vaccine approach has promise and that multicomponent vaccines based in the same system merit further investigation.

Download Full-text

Effect of CD8+ Lymphocyte Depletion on Virus Containment after Simian Immunodeficiency Virus SIVmac251 Challenge of Live Attenuated SIVmac239Δ3-Vaccinated Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.79.13.8131-8141.2005 ◽

2005 ◽

Vol 79 (13) ◽

pp. 8131-8141 ◽

Cited By ~ 94

Author(s):

Jörn E. Schmitz ◽

R. Paul Johnson ◽

Harold M. McClure ◽

Kelledy H. Manson ◽

Michael S. Wyand ◽

...

Keyword(s):

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Intravenous Route ◽

Partial Control ◽

Challenge Virus ◽

Lymphocyte Depletion ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Cellular Immune

ABSTRACT Although live attenuated vaccines can provide potent protection against simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus challenges, the specific immune responses that confer this protection have not been determined. To test whether cellular immune responses mediated by CD8+ lymphocytes contribute to this vaccine-induced protection, we depleted rhesus macaques vaccinated with the live attenuated virus SIVmac239Δ3 of CD8+ lymphocytes and then challenged them with SIVmac251 by the intravenous route. While vaccination did not prevent infection with the pathogenic challenge virus, the postchallenge levels of virus in the plasmas of vaccinated control animals were significantly lower than those for unvaccinated animals. The depletion of CD8+ lymphocytes at the time of challenge resulted in virus levels in the plasma that were intermediate between those of the vaccinated and unvaccinated controls, suggesting that CD8+ cell-mediated immune responses contributed to protection. Interestingly, at the time of challenge, animals expressing the Mamu-A*01 major histocompatibility complex class I allele showed significantly higher frequencies of SIV-specific CD8+ T-cell responses and lower neutralizing antibody titers than those in Mamu-A*01 − animals. Consistent with these findings, the depletion of CD8+ lymphocytes abrogated vaccine-induced protection, as judged by the peak postchallenge viremia, to a greater extent in Mamu-A*01 + than in Mamu-A*01 − animals. The partial control of postchallenge viremia after CD8+ lymphocyte depletion suggests that both humoral and cellular immune responses induced by live attenuated SIV vaccines can contribute to protection against a pathogenic challenge and that the relative contribution of each of these responses to protection may be genetically determined.

Download Full-text

Effective Induction of Simian Immunodeficiency Virus-Specific Systemic and Mucosal Immune Responses in Primates by Vaccination with Proviral DNA Producing Intact but Noninfectious Virions

Journal of Virology ◽

10.1128/jvi.74.22.10514-10522.2000 ◽

2000 ◽

Vol 74 (22) ◽

pp. 10514-10522 ◽

Cited By ~ 50

Author(s):

Shainn-Wei Wang ◽

Pamela A. Kozlowski ◽

Gretchen Schmelz ◽

Kelledy Manson ◽

Michael S. Wyand ◽

...

Keyword(s):

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Dna Vaccine ◽

Cytotoxic T Lymphocyte ◽

Natural Infection ◽

Immunoglobulin A ◽

Rectal Mucosa ◽

Immunodeficiency Virus ◽

Mucosal Immune Responses ◽

Lymphocyte Responses

ABSTRACT We report a pilot evaluation of a DNA vaccine producing genetically inactivated simian immunodeficiency virus (SIV) particles in primates, with a focus on eliciting mucosal immunity. Our results demonstrate that DNA vaccines can be used to stimulate strong virus-specific mucosal immune responses in primates. The levels of immunoglobulin A (IgA) detected in rectal secretions of macaques that received the DNA vaccine intradermally and at the rectal mucosa were the most striking of all measured immune responses and were higher than usually achieved through natural infection. However, cytotoxic T lymphocyte responses were generally low and sporadically present in different animals. Upon rectal challenge with cloned SIVmac239, resistance to infection was observed, but some animals with high SIV-specific IgA levels in rectal secretions became infected. Our results suggest that high levels of IgA alone are not sufficient to prevent the establishment of chronic infection, although mucosal IgA responses may have a role in reducing the infectivity of the initial viral inoculum.

Download Full-text