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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunologic basis for the potential enhanced HIV-1 acquisition in adenovirus serotype 5 (Ad5)-seropositive individuals who received the Merck recombinant Ad5 HIV-1 vaccine in the STEP study remains unclear. Here we show that baseline Ad5-specific neutralizing antibodies are not correlated with Ad5-specific T lymphocyte responses and that Ad5-seropositive subjects do not develop higher vector-specific cellular immune responses as compared with Ad5-seronegative subjects after vaccination. These findings challenge the hypothesis that activated Ad5-specific T lymphocytes were the cause of the potential enhanced HIV-1 susceptibility in the STEP study.
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PMID:Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans. 1962 Sep 61

The mechanisms underlying possible increased HIV-1 acquisition in adenovirus 5 (Ad5)-seropositive subjects vaccinated with Ad5-HIV-1 vectors in the Merck STEP trial remain unclear. We find that Ad5 serostatus does not predict Ad5-specific CD4(+) T cell frequency, and we did not observe durable significant differences in Ad5-specific CD4(+) T cells between Ad5-seropositive and Ad5-seronegative subjects after vaccination. These findings indicate no causative role for Ad5-specific CD4(+) T cells in increasing HIV-1 susceptibility in the STEP trial.
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PMID:Baseline Ad5 serostatus does not predict Ad5 HIV vaccine-induced expansion of adenovirus-specific CD4+ T cells. 1962 Sep 62

Infection with HIV type 1 (HIV-1), the causative agent of AIDS, is one of the most catastrophic pandemics to affect human healthcare in the latter 20th century. The best hope of controlling this pandemic is the development of a successful prophylactic vaccine. However, to date, this goal has proven to be exceptionally elusive. The recent failure of an experimental vaccine in a phase IIb study, named the STEP trial, intended solely to elicit cell-mediated immune responses against HIV-1, has highlighted the need for a balanced immune response consisting of not only cellular immunity but also a broad and potent humoral antibody response that can prevent infection with HIV-1. This article reviews the efforts made up to this point to elicit such antibody responses, especially with regard to the use of a DNA prime-protein boost regimen, which has been proven to be a highly effective platform for the induction of neutralizing antibodies in both animal and early-phase human studies.
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PMID:Progress on the induction of neutralizing antibodies against HIV type 1 (HIV-1). 1962 66

In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing alpha(4)beta(7) integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-gamma production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.
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PMID:Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1. 1991 60

The road to the discovery of a vaccine for HIV has been arduous and will continue to be difficult over the ensuing twenty years. Most vaccines are developed by inducing neutralizing antibodies against the target pathogen or by using attenuated strains of the particular pathogen to engender a variety of protective immune responses. Unfortunately, simple methods of generating anti-HIV antibodies have already failed in a phase III clinical trial. While attenuated SIV variants work well against homologous challenges in non-human primates, the potential for reversion to a more pathogenic virus and recombination with challenge viruses will preclude the use of attenuated HIV in the field. It has been exceedingly frustrating to vaccinate for HIV-specific neutralizing antibodies given the enormous diversity of the Envelope (Env) glycoprotein and its well-developed glycan shield. However, there are several antibodies that will neutralize many different strains of HIV and inducing these types of antibodies in vaccinees remains the goal of a vigorous effort to develop a vaccine for HIV based on neutralizing antibodies. Given the difficulty in generating broadly reactive neutralizing antibodies, the HIV vaccine field has turned its attention to inducing T cell responses against the virus using a variety of vectors. Unfortunately, the results from Merck's phase IIb STEP trial proved to be disappointing. Vaccinees received Adenovirus type 5 (Ad5) expressing Gag, Pol, and Nef of HIV. This vaccine regimen failed to either prevent infection or reduce the level of HIV replication after challenge. These results mirrored those in non-human primate testing of Ad5 using rigorous SIV challenge models. This review will focus on recent developments in HIV vaccine development. We will deal largely with attempts to develop a T cell-based vaccine using the non-human primate SIV challenge model.
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PMID:Is an HIV vaccine possible? 2023 96

Sexually transmitted infections (STIs) are a major cause of morbidity and mortality worldwide. Although a vaccine is available for HPV, no effective vaccines exist for the HIV-1 and HSV-2 viral pathogens, and there are no cures for these infections. Furthermore, recent setbacks in clinical trials, such as the failure of the STEP trial to prevent HIV-1 infection, have emphasized the need to develop alternative approaches to interrupt the transmission of these pathogens. One alternative strategy is represented by the use of topically applied microbicides, and such agents are being developed against various viruses. RNAi-based microbicides have recently been demonstrated to prevent HSV-2 transmission, and may be useful for targeting multiple STIs. In this review, microbicides that are under development for the prevention of STIs are described, with a focus on topically applied microbicidal siRNAs.
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PMID:siRNA-based topical microbicides targeting sexually transmitted infections. 2037 63

The development of a safe and effective HIV vaccine remains the best hope to control the global HIV epidemic. So far, the different strategies tried for vaccine development have led to disappointing results. The first attempted strategy involved trying to raise neutralizing antibodies to inactivate the virus and prevent infection. Both of Vaxgen's VAX004 and VAX003 phase 3 trials made use of this approach but ultimately failed. Given the difficulties encountered, the focus then shifted to the cell mediated arm of the immune system, the T lymphocytes. However, the phase 2 STEP study, which was aimed to stimulate cell-mediated immunity, was halted in 2007 because it failed to prevent infection and there was an increased incidence of HIV infection in vaccinated individuals. Many researchers now believe that vaccine candidates need to induce both sustained broadly neutralizing antibodies and a strong cell-mediated response. Therefore, attention is now focused on the prime-boost approach: a DNA or vector vaccine to elicit cytotoxic T cells that destroy infected cells followed by a subunit vaccine to induce neutralizing antibodies. RV144, the largest ever HIV vaccine trial, used a prime-boost combination vaccine, which was shown to be safe and modestly effective. The ongoing RV152 study will provide more information on the modest degree of efficacy of the RV144 vaccine with results expected in 2013. Finally, the ongoing HVTN 505 trial also makes use of the prime-boost strategy and is expected to provide a better understanding of T-cell-based vaccines. In this review, we discuss the results of all the above-mentioned trials and consider whether an HIV vaccine needs to induce both humoral and cellular immunity to be effective.
Curr HIV Res 2010 Sep
PMID:An effective HIV vaccine: A combination of humoral and cellular immunity? 2063 79

A major hurdle in the development of a global HIV-1 vaccine is viral diversity. For close to three decades, HIV vaccine development has focused on either the induction of T cell immune responses or antibody responses, and only rarely on both components. After the failure of the STEP trial, the scientific community concluded that a T cell-based vaccine would likely not be protective if the T cell immune responses were elicited against only a few dominant epitopes. Similarly, for vaccines focusing on antibody responses, one of the main criticisms after VaxGen's failed Phase III trials was on the limited antigen breadth included in the two formulations used. The successes of polyvalent vaccine approaches against other antigenically variable pathogens encourage implementation of the same approach for the design of HIV-1 vaccines. A review of the existing HIV-1 vaccination approaches based on the polyvalent principle is included here to provide a historical perspective for the current effort of developing a polyvalent HIV-1 vaccine. Results summarized in this review provide a clear indication that the polyvalent approach is a viable one for the future development of an effective HIV vaccine.
Curr HIV Res 2010 Dec
PMID:Polyvalent AIDS vaccines. 2105 50

Adenovirus (Ad) is still under extensive investigation as a vector for HIV vaccination; however, one possible explanation for the failure of Merck's STEP trial is the relatively weak immunogenicity of replication-defective Ad vectors. In this study, a novel strategy to enhance the immunogenicity of replication-defective Ad-based HIV vaccines was developed. First, a recombinant plasmid expressing adenoviral E1 protein (pVAX-E1) was constructed to complement the E1-deleted replication-defective Ad vectors in trans. Then, the immunogenicity of the vaccine regimen of Ad5-HIV gag plus pVAX-E1 plasmid was assessed in rhesus macaques. Compared with traditional administration of Ad-based vectors alone, the results showed that our strategy elicited a more sustained and robust HIV gag-specific cellular response and enhanced long-term proliferation of CD4(+) and CD8(+) T lymphocytes. This strategy represents a proof-of-concept that enhances the immunogenicity of replication-defective Ad-based vectors, and it exemplifies the useful implications for Ad-based HIV vaccines and other vaccines.
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PMID:Short communication: enhancement of immunogenicity of replication-defective adenovirus-based human immunodeficiency virus vaccines in rhesus monkeys. 2108 37

We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.
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PMID:Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial. 2135 27


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