Genetically identical primate modelling systems for HIV vaccines

There is an urgent need for a safe and effective vaccine to prevent human immunodeficiency virus (HIV) infection. Several HIV vaccine candidates have shown promise, but many concerns regarding the safety and efficacy of current vaccines remain. A major hindrance in HIV vaccine development is a poor understanding of precisely what functions HIV vaccines are required to perform in order to protect humans from HIV-1. Only higher primates (i.e. macaques, chimpanzees and humans) are susceptible to HIV-1 or the closely related virus ‘simian immunodeficiency virus’. These species are outbred and there are remarkable genetic differences in both the immune responses to vaccines and their susceptibility to infection. The development of genetically identical macaques would be a major step towards dissecting what immune responses are required to protect from HIV infection. For example, live attenuated HIV-1 vaccines are likely to be highly efficacious, but will induce disease in a substantial proportion of recipients. Defining why a live attenuated vaccine is effective should allow safer vaccines to be developed, retaining only the immunologic properties of an effective vaccine. The reduction in ‘background genetic noise’ obtained by studying genetically identical primates would provide concise answers to critical HIV vaccine issues, by studying a minimal number of animals. Such an approach could potentially be employed in other diseases where non-human primates are the only available model. Small studies can be performed where identical twins are generated by embryo bisection; however, larger studies where multiple immune parameters are simultaneously evaluated would be facilitated by cloning technology. Despite the technical difficulties to be overcome, the potential gains in human health from the development of genetically identical non-human primates are worthy of careful consideration.

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Contrasting Adult and Infant Immune Responses to HIV Infection and Vaccination

Clinical and Vaccine Immunology ◽

10.1128/cvi.00565-15 ◽

2015 ◽

Vol 23 (2) ◽

pp. 84-94 ◽

Cited By ~ 22

Author(s):

David R. Martinez ◽

Sallie R. Permar ◽

Genevieve G. Fouda

Keyword(s):

Immune Responses ◽

Hiv Infection ◽

Vaccine Efficacy ◽

Neutralizing Antibody ◽

Hiv Vaccine ◽

Antibody Responses ◽

Hiv Vaccines ◽

Vaccine Candidates ◽

Protective Antibodies ◽

Pediatric Populations

ABSTRACTExtensive studies have demonstrated that infant immune responses are distinct from those of adults. Despite these differences, infant immunization can elicit protective immune responses at levels comparable to or, in some cases, higher than adult immune responses to many vaccines. To date, only a few HIV vaccine candidates have been tested in infant populations, and none of them evaluated vaccine efficacy. Recent exciting studies showing that HIV-infected infants can develop broad neutralizing antibody responses and that some HIV vaccine regimens can elicit high levels of potentially protective antibodies in infants provide support for the development and testing of HIV vaccines in pediatric populations. In this review, we discuss the differences in adult and infant immune responses in the setting of HIV infection and vaccination.

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Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome

Journal of Virology ◽

10.1128/jvi.00979-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Mauricio A. Martins ◽

Lucas Gonzalez-Nieto ◽

Michael J. Ricciardi ◽

Varian K. Bailey ◽

Christine M. Dang ◽

...

Keyword(s):

T Cells ◽

Virus Infection ◽

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Vaccine Efficacy ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Hiv Vaccine ◽

Partial Control ◽

Immunodeficiency Virus

ABSTRACT Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.

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Outcome of Simian-Human Immunodeficiency Virus Strain 89.6p Challenge following Vaccination of Rhesus Macaques with Human Immunodeficiency Virus Tat Protein

Journal of Virology ◽

10.1128/jvi.76.8.3800-3809.2002 ◽

2002 ◽

Vol 76 (8) ◽

pp. 3800-3809 ◽

Cited By ~ 45

Author(s):

Peter Silvera ◽

Max W. Richardson ◽

Jack Greenhouse ◽

Jake Yalley-Ogunro ◽

Nigel Shaw ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Vaccine Development ◽

Rhesus Macaques ◽

Biologically Active ◽

Cell Counts ◽

Human Immunodeficiency Virus Strain ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The regulatory proteins Nef, Rev, and Tat of human immunodeficiency virus type 1 (HIV-1) are attractive targets for vaccine development, since induction of effective immune responses targeting these early proteins may best control virus replication. Here we investigated whether vaccination with biologically active Tat or inactive Tat toxoid derived from HIV-1IIIB and simian-human immunodeficiency virus (SHIV) strain 89.6p would induce protective immunity in rhesus macaques. Vaccination induced high titers of anti-Tat immunoglobulin G in all immunized animals by week 7, but titers were somewhat lower in the 89.6p Tat group. Dominant B-cell epitopes mapped to the amino terminus, the basic domain, and the carboxy-terminal region. Tat-specific T-helper responses were detected in 50% of immunized animals. T-cell epitopes appeared to map within amino acids (aa) 1 to 24 and aa 37 to 66. In addition, Tat-specific gamma interferon responses were detected in CD4+ and/or CD8+ T lymphocytes in 11 of 16 immunized animals on the day of challenge. However, all animals became infected upon intravenous challenge with 30 50% minimal infective doses of SHIV 89.6p, and there were no significant differences in viral loads or CD4+ T-cell counts between immunized and control animals. Thus, vaccination with HIV-1IIIB or SHIV 89.6p Tat or with Tat toxoid preparations failed to confer protection against SHIV 89.6p infection despite robust Tat-specific humoral and cellular immune responses in some animals. Given its apparent immunogenicity, Tat may be more effective as a component of a cocktail vaccine in combination with other regulatory and/or structural proteins of HIV-1.

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Preventive HIV Vaccines-Leveraging on Lessons from the Past to Pave the Way Forward

Vaccines ◽

10.3390/vaccines9091001 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1001

Author(s):

Parveen Sobia ◽

Derseree Archary

Keyword(s):

Immune Responses ◽

Female Genital Tract ◽

Hiv Infections ◽

Hiv Vaccine ◽

Effective Vaccine ◽

Hiv Vaccines ◽

The Past ◽

Sex With Men ◽

Exposure Prophylaxis ◽

Female Genital

Almost four decades on, since the 1980’s, with hundreds of HIV vaccine candidates tested in both non-human primates and humans, and several HIV vaccines trials later, an efficacious HIV vaccine continues to evade us. The enormous worldwide genetic diversity of HIV, combined with HIV’s inherent recombination and high mutation rates, has hampered the development of an effective vaccine. Despite the advent of antiretrovirals as pre-exposure prophylaxis and preventative treatment, which have shown to be effective, HIV infections continue to proliferate, highlighting the great need for a vaccine. Here, we provide a brief history for the HIV vaccine field, with the most recent disappointments and advancements. We also provide an update on current passive immunity trials, testing proof of the concept of the most clinically advanced broadly neutralizing monoclonal antibodies for HIV prevention. Finally, we include mucosal immunity, the importance of vaccine-elicited immune responses and the challenges thereof in the most vulnerable environment–the female genital tract and the rectal surfaces of the gastrointestinal tract for heterosexual and men who have sex with men transmissions, respectively.

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Human Immunodeficiency Virus Type 1 Clade B Superinfection: Evidence for Differential Immune Containment of Distinct Clade B Strains

Journal of Virology ◽

10.1128/jvi.79.2.860-868.2005 ◽

2005 ◽

Vol 79 (2) ◽

pp. 860-868 ◽

Cited By ~ 61

Author(s):

Otto O. Yang ◽

Eric S. Daar ◽

Beth D. Jamieson ◽

Arumugam Balamurugan ◽

Davey M. Smith ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Vaccine Development ◽

Effective Vaccine ◽

Set Point ◽

Clade B ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Sequential infection with different strains of human immunodeficiency virus type 1 (HIV-1) is a rarely identified phenomenon with important implications for immunopathogenesis and vaccine development. Here, we identify an individual whose good initial control of viremia was lost in association with reduced containment of a superinfecting strain. Subject 2030 presented with acute symptoms of HIV-1 infection with high viremia and an incomplete seroconversion as shown by Western blotting. A low set point of viremia (∼1,000 HIV-1 copies/ml) was initially established without drug therapy, but a new higher set point (∼40,000 HIV-1 copies/ml) manifested about 5 months after infection. Drug susceptibility testing demonstrated a multidrug-resistant virus initially but a fully sensitive virus after 5 months, and an analysis of pol genotypes showed that these were two phylogenetically distinct strains of virus (strains A and B). Replication capacity assays suggested that the outgrowth of strain B was not due to higher fitness conferred by pol, and env sequences indicated that the two strains had the same R5 coreceptor phenotype. Delineation of CD8+-T-lymphocyte responses against HIV-1 showed a striking pattern of decay of the initial cellular immune responses after superinfection, followed by some adaptation of targeting to new epitopes. An examination of targeted sequences suggested that differences in the recognized epitopes contributed to the poor immune containment of strain B. In conclusion, the rapid overgrowth of a superinfecting strain of HIV-1 of the same subtype raises major concerns for effective vaccine development.

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Mycobacterial Codon Optimization Enhances Antigen Expression and Virus-Specific Immune Responses in Recombinant Mycobacterium bovis Bacille Calmette-Guérin Expressing Human Immunodeficiency Virus Type 1 Gag

Journal of Virology ◽

10.1128/jvi.79.14.8716-8723.2005 ◽

2005 ◽

Vol 79 (14) ◽

pp. 8716-8723 ◽

Cited By ~ 25

Author(s):

Masaru Kanekiyo ◽

Kazuhiro Matsuo ◽

Makiko Hamatake ◽

Takaichi Hamano ◽

Takeaki Ohsu ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Mycobacterium Bovis ◽

Vaccine Development ◽

Antigen Expression ◽

Immunodeficiency Virus ◽

Cell Induction ◽

P24 Antigen ◽

Hiv 1

ABSTRACT Although its potential for vaccine development is already known, the introduction of recombinant human immunodeficiency virus (HIV) genes to Mycobacterium bovis bacille Calmette-Guérin (BCG) has thus far elicited only limited responses. In order to improve the expression levels, we optimized the codon usage of the HIV type 1 (HIV-1) p24 antigen gene of gag (p24 gag) and established a codon-optimized recombinant BCG (rBCG)-p24 Gag which expressed a 40-fold-higher level of p24 Gag than did that of nonoptimized rBCG-p24 Gag. Inoculation of mice with the codon-optimized rBCG-p24 Gag elicited effective immunity, as evidenced by virus-specific lymphocyte proliferation, gamma interferon ELISPOT cell induction, and antibody production. In contrast, inoculation of animals with the nonoptimized rBCG-p24 Gag induced only low levels of immune responses. Furthermore, a dose as small as 0.01 mg of the codon-optimized rBCG per animal proved capable of eliciting immune responses, suggesting that even low doses of a codon-optimized rBCG-based vaccine could effectively elicit HIV-1-specific immune responses.

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Antibody-Dependent Cellular Cytotoxicity and NK Cell-Driven Immune Escape in HIV Infection: Implications for HIV Vaccine Development

Advances in Virology ◽

10.1155/2012/637208 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Gamze Isitman ◽

Ivan Stratov ◽

Stephen J. Kent

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Vaccine Development ◽

Immune Escape ◽

Nk Cell ◽

Hiv Vaccine ◽

Cellular Cytotoxicity ◽

Antibody Dependent Cellular Cytotoxicity ◽

Neutralising Antibodies ◽

Hiv 1

The HIV-1 genome is malleable and a difficult target tot vaccinate against. It has long been recognised that cytotoxic T lymphocytes and neutralising antibodies readily select for immune escape HIV variants. It is now also clear that NK cells can also select for immune escape. NK cells force immune escape through both direct Killer-immunoglobulin-like receptor (KIR)-mediated killing as well as through facilitating antibody-dependent cellular cytotoxicity (ADCC). These newer finding suggest NK cells and ADCC responses apply significant pressure to the virus. There is an opportunity to harness these immune responses in the design of more effective HIV vaccines.

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Magnitude and Frequency of Cytotoxic T-Lymphocyte Responses: Identification of Immunodominant Regions of Human Immunodeficiency Virus Type 1 Subtype C

Journal of Virology ◽

10.1128/jvi.76.20.10155-10168.2002 ◽

2002 ◽

Vol 76 (20) ◽

pp. 10155-10168 ◽

Cited By ~ 83

Author(s):

V. Novitsky ◽

H. Cao ◽

N. Rybak ◽

P. Gilbert ◽

M. F. McLane ◽

...

Keyword(s):

Immune Responses ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Population Level ◽

Hiv Vaccine ◽

Subtype C ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT A systematic analysis of immune responses on a population level is critical for a human immunodeficiency virus type 1 (HIV-1) vaccine design. Our studies in Botswana on (i) molecular analysis of the HIV-1 subtype C (HIV-1C) epidemic, (ii) frequencies of major histocompatibility complex class I HLA types, and (iii) cytotoxic T-lymphocyte (CTL) responses in the course of natural infection allowed us to address HIV-1C-specific immune responses on a population level. We analyzed the magnitude and frequency of the gamma interferon ELISPOT-based CTL responses and translated them into normalized cumulative CTL responses. The introduction of population-based cumulative CTL responses reflected both (i) essentials of the predominant virus circulating locally in Botswana and (ii) specificities of the genetic background of the Botswana population, and it allowed the identification of immunodominant regions across the entire HIV-1C. The most robust and vigorous immune responses were found within the HIV-1C proteins Gag p24, Vpr, Tat, and Nef. In addition, moderately strong responses were scattered across Gag p24, Pol reverse transcriptase and integrase, Vif, Tat, Env gp120 and gp41, and Nef. Assuming that at least some of the immune responses are protective, these identified immunodominant regions could be utilized in designing an HIV vaccine candidate for the population of southern Africa. Targeting multiple immunodominant regions should improve the overall vaccine immunogenicity in the local population and minimize viral escape from immune recognition. Furthermore, the analysis of HIV-1C-specific immune responses on a population level represents a comprehensive systematic approach in HIV vaccine design and should be considered for other HIV-1 subtypes and/or different geographic areas.

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Pseudovirion Particle Production by Live Poxvirus Human Immunodeficiency Virus Vaccine Vector Enhances Humoral and Cellular Immune Responses

Journal of Virology ◽

10.1128/jvi.79.9.5537-5547.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5537-5547 ◽

Cited By ~ 17

Author(s):

Xuemin Chen ◽

Michael T. Rock ◽

Jason Hammonds ◽

James Tartaglia ◽

Ayumi Shintani ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Particle Production ◽

T Cell Responses ◽

Particle Formation ◽

Hiv Vaccine ◽

Hiv Vaccines ◽

Cell Responses ◽

Immunodeficiency Virus

ABSTRACT Live-vector-based human immunodeficiency virus (HIV) vaccines are an integral part of a number of HIV vaccine regimens currently under evaluation. Live vectors that carry an intact gag gene are capable of eliciting HIV pseudovirion particle formation from infected host cells. The impact of pseudovirion particle formation on the immune response generated by live HIV vaccine vectors has not been established. In this study, a canarypox HIV vaccine candidate vector expressing HIV gag and env genes, vCP205, was modified by the introduction of a glycine-to-alanine coding change in the N-terminal myristylation site of gag to create Myr− vCP205. This substitution effectively eliminated particle formation without altering the level of protein production. vCP205 and Myr− vCP205 were then directly compared for the ability to induce HIV-specific immune responses in mice. The particle-competent vector vCP205 elicited higher levels of CD8+ T-cell responses, as indicated by gamma interferon enzyme-linked immunospot (ELISPOT) assay and intracellular cytokine staining. Humoral responses to Gag and Env were also markedly higher from animals immunized with the particle-competent vector. Furthermore, HIV-specific CD4+ T-cell responses were greater among animals immunized with the particle-competent vector. Using a human dendritic cell model of antigen presentation in vitro, vCP205 generated greater ELISPOT responses than Myr− vCP205. These results demonstrate that pseudovirion particle production by live-vector HIV vaccines enhances HIV-specific cellular and humoral immune responses.

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Integrated analysis of lncRNA, miRNA and mRNA profiles reveals potential lncRNA functions during early HIV infection

Journal of Translational Medicine ◽

10.1186/s12967-021-02802-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lianwei Ma ◽

Hui Zhang ◽

Yue Zhang ◽

Hailong Li ◽

Minghui An ◽

...

Keyword(s):

Hiv Infection ◽

Immune Activation ◽

Expression Profiles ◽

Critical Role ◽

Differentially Expressed ◽

Integrated Analysis ◽

Target Mrnas ◽

Immunodeficiency Virus ◽

Mirna Sequencing ◽

Hiv 1

Abstract Background Long noncoding RNAs (lncRNAs) can regulate gene expression in a cis-regulatory fashion or as “microRNA sponges”. However, the expression and functions of lncRNAs during early human immunodeficiency virus (HIV) infection (EHI) remain unclear. Methods 3 HAART-naive EHI patients and 3 healthy controls (HCs) were recruited in this study to perform RNA sequencing and microRNA (miRNA) sequencing. The expression profiles of lncRNAs, mRNAs and miRNAs were obtained, and the potential roles of lncRNAs were analysed based on discovering lncRNA cis-regulatory target mRNAs and constructing lncRNA–miRNA–mRNA competing endogenous RNA (ceRNA) networks. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on 175 lncRNA-associated differentially expressed (DE) mRNAs to investigate the potential functions of DE lncRNAs in ceRNA networks. Results A total of 242 lncRNAs, 1240 mRNAs and 21 mature known miRNAs were determined as differentially expressed genes in HAART-naive EHI patients compared to HCs. Among DE lncRNAs, 44 lncRNAs were predicted to overlap with 41 target mRNAs, and 107 lncRNAs might regulate their nearby DE mRNAs. Two DE lncRNAs might regulate their cis-regulatory target mRNAs BTLA and ZAP70, respectively, which were associated with immune activation. In addition, the ceRNA networks comprised 160 DE lncRNAs, 21 DE miRNAs and 175 DE mRNAs. Seventeen DE lncRNAs were predicted to regulate HIF1A and TCF7L2, which are involved in the process of HIV-1 replication. Twenty DE lncRNAs might share miRNA response elements (MREs) with FOS, FOSB and JUN, which are associated with both immune activation and HIV-1 replication. Conclusions This study revealed that lncRNAs might play a critical role in HIV-1 replication and immune activation during EHI. These novel findings are helpful for understanding of the pathogenesis of HIV infection and provide new insights into antiviral therapy.

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