Biomedical subjects

David C Montefiori

Publications and source records attributed to David C Montefiori.

At least 19 recordsLinked to original sources

PubMed2016

Immune perturbations in HIV-1-infected individuals who make broadly neutralizing antibodies.

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. bnAbs occur in some HIV-1-infected individuals and frequently have characteristics of autoantibodies. We have studied cohorts of HIV-1-infected individuals who made bnAbs and compared them with those who did not do so, and determined immune traits associated with the ability to produce bnAbs. HIV-1-infected individuals with bnAbs had a higher frequency of blood autoantibodies, a lower frequency of regulatory CD4+ T cells, a higher frequency of circulating memory T follicular helper CD4+ cells, and a higher T regulatory cell level of programmed cell death-1 expression compared with HIV-1-infected individuals without bnAbs. Thus, induction of HIV-1 bnAbs may require vaccination regimens that transiently mimic immunologic perturbations in HIV-1-infected individuals.

Journal Article↗

PubMed2007

Phase 2 study of an HIV-1 canarypox vaccine (vCP1452) alone and in combination with rgp120: negative results fail to trigger a phase 3 correlates trial.

BACKGROUND: A goal of T-cell HIV vaccines is to define the correlation between a vaccine-induced immune response and protection from HIV infection. We conducted a phase 2 trial to determine if a canarypox vaccine candidate (vCP1452) administered with rgp120 subunit protein would "qualify" for a trial to define a correlate of efficacy. METHODS: A total of 330 healthy volunteers were enrolled into 4 groups: 120 received vCP1452 alone (0, 1, 3, and 6 months), 120 received vCP1452 with 2 different regimens of rgp120 coadministration, and 90 received placebo. HIV-specific antibody responses were measured by enzyme-linked immunoassay (ELISA) and neutralizing activity. T-cell responses were measured by chromium release and interferon-gamma (IFNgamma) enzyme-linked immunospot (ELISpot) assay. RESULTS: Significant neutralizing antibody responses to the HIV MN strain were detected in all vaccine groups, with net responses ranging from 57% (95% confidence interval [CI]: 40% to 71%) to 94% (95% CI: 85% to 99%). Net cumulative HIV-specific CD8 IFNgamma ELISpot assay responses were 13% (95% CI: -1% to 26%) for recipients of vCP1452 alone and 16% (95% CI: 2% to 29%) for recipients of vCP1452 plus rgp120. CONCLUSIONS: Overall, the HIV-specific CD8 cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8 CTL frequency of 30%.

AIDS Vaccines↗

PubMed2007

A replication-competent adenovirus-human immunodeficiency virus (Ad-HIV) tat and Ad-HIV env priming/Tat and envelope protein boosting regimen elicits enhanced protective efficacy against simian/human immunodeficiency virus SHIV89.6P challenge in rhesus macaques.

We previously demonstrated that replication-competent adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinant prime/protein boost regimens elicit potent immunogenicity and strong, durable protection of rhesus macaques against SIV(mac251). Additionally, native Tat vaccines have conferred strong protection against simian/human immunodeficiency virus SHIV(89.6P) challenge of cynomolgus monkeys, while native, inactivated, or vectored Tat vaccines have failed to elicit similar protective efficacy in rhesus macaques. Here we asked if priming rhesus macaques with replicating Ad-human immunodeficiency virus (HIV) tat and boosting with the Tat protein would elicit protection against SHIV(89.6P). We also evaluated a Tat/Env regimen, adding an Ad-HIV env recombinant and envelope protein boost to test whether envelope antibodies would augment acute-phase protection. Further, expecting cellular immunity to enhance chronic viremia control, we tested a multigenic group: Ad-HIV tat, -HIV env, -SIV gag, and -SIV nef recombinants and Tat, Env, and Nef proteins. All regimens were immunogenic. A hierarchy was observed in enzyme-linked immunospot responses (with the strongest response for Env, followed by Gag, followed by Nef, followed by Tat) and antibody titers (with the highest titer for Env, followed by Tat, followed by Nef, followed by Gag). Following intravenous SHIV(89.6P) challenge, all macaques became infected. Compared to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by approximately 1 log (P = 0.017), and both the multigenic and Tat/Env groups reduced chronic viremia by 3 and 4 logs, respectively, compared to controls (multigenic, P = 0.0003; Tat/Env, P < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group (P = 0.014) was correlated with Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV(89.6P)-neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens.

Adenoviridae↗

PubMed2006

An adenovirus-based HIV subtype B prime/boost vaccine regimen elicits antibodies mediating broad antibody-dependent cellular cytotoxicity against non-subtype B HIV strains.

Although HIV subtype B predominates in North America and Western Europe, most HIV infections worldwide are non-subtype B. Globally effective AIDS vaccines need to elicit broad immunity against multiple HIV strains. In this study, 10 chimpanzees were intranasally primed sequentially with adenovirus type 5 (Ad5)- and Ad7-HIVMNenv/rev recombinants and boosted twice intramuscularly with heterologous oligomeric HIVSF162 gp140DeltaV2 protein in MF59 adjuvant. Sera were evaluated for binding, neutralizing, and antibody-dependent cellular cytotoxicity (ADCC) against HIV clades A, B, C, and CRF01_AE. The vaccine regimen elicited high-titered HIV subtype A, B, C and CRF01_AE gp120-binding antibodies. Sera from 7 of 10 vaccinated chimpanzees cross-neutralized the heterologous South African subtype C primary HIVTV-1 isolate. Significant cross-clade neutralization against other subtype A, C and E isolates was not observed. Sera from all animals mediated ADCC of cells coated with gp120 from HIV subtypes A and B. Nine of 10 animals also exhibited ADCC activity against HIV subtype C and CRF01_AE gp120-coated targets. This subtype B Ad-HIV recombinant prime/envelope protein boost regimen is a promising approach for eliciting broad ADCC activity against diverse HIV clades. Incorporating additional non-subtype B envelope genes and protein boosts in a multivalent strategy may be required to elicit broader neutralizing antibodies against non-subtype B HIV strains.

AIDS Vaccines↗

PubMed2006

A plea for justice for jailed medical workers.

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Child↗

PubMed2006

A group M consensus envelope glycoprotein induces antibodies that neutralize subsets of subtype B and C HIV-1 primary viruses.

HIV-1 subtype C is the most common HIV-1 group M subtype in Africa and many parts of Asia. However, to date HIV-1 vaccine candidate immunogens have not induced potent and broadly neutralizing antibodies against subtype C primary isolates. We have used a centralized gene strategy to address HIV-1 diversity and generated a group M consensus envelope gene with shortened consensus variable loops (CON-S) for comparative studies with wild-type (WT) Env immunogens. Our results indicate that the consensus HIV-1 group M CON-S Env elicited cross-subtype neutralizing antibodies of similar or greater breadth and titer than the WT Envs tested, indicating the utility of a centralized gene strategy. Our study also shows the feasibility of iterative improvements in Env immunogenicity by rational design of centralized genes.

AIDS Vaccines↗

PubMed2006

Time dependence of protective post-exposure prophylaxis with human monoclonal antibodies against pathogenic SHIV challenge in newborn macaques.

In a primate model of postnatal virus transmission, we have previously shown that 1 h post-exposure prophylaxis (PEP) with a triple combination of neutralizing monoclonal antibodies (nmAbs) conferred sterilizing protection to neonatal macaques against oral challenge with pathogenic simian-human immunodeficiency virus (SHIV). Here, we show that nmAbs can also partially protect SHIV-exposed newborn macaques against infection or disease, when given as 12 or 24 h PEP, respectively. This work delineates the potential and the limits of passive immunoprophylaxis with nmAbs. Even though 24 h PEP with nmAbs did not provide sterilizing immunity to neonatal monkeys, it contained viremia and protected infants from acute disease. Taken together with our results from other PEP studies, these data show that the success of passive immunization depends on the nmAb potency/dose and the time window between virus exposure and start of immunotherapy.

Animals↗

PubMed2006

Genetic and neutralization properties of subtype C human immunodeficiency virus type 1 molecular env clones from acute and early heterosexually acquired infections in Southern Africa.

A standard panel of subtype C human immunodeficiency virus type 1 (HIV-1) Env-pseudotyped viruses was created by cloning, sequencing, and characterizing functional gp160 genes from 18 acute and early heterosexually acquired infections in South Africa and Zambia. In general, the gp120 region of these clones was shorter (most evident in V1 and V4) and less glycosylated compared to newly transmitted subtype B viruses, and it was underglycosylated but no different in length compared to chronic subtype C viruses. The gp120s also exhibited low amino acid sequence variability (12%) in V3 and high variability (39%) immediately downstream of V3, a feature shared with newly transmitted subtype B viruses and chronic viruses of both subtypes. When tested as Env-pseudotyped viruses in a luciferase reporter gene assay, all clones possessed an R5 phenotype and resembled primary isolates in their sensitivity to neutralization by HIV-1-positive plasmas. Results obtained with a multisubtype plasma panel suggested partial subtype preference in the neutralizing antibody response to infection. The clones were typical of subtype C in that all were resistant to 2G12 (associated with loss of N-glycosylation at position 295) and most were resistant to 2F5, but all were sensitive to 4E10 and many were sensitive to immunoglobulin G1b12. Finally, conserved neutralization epitopes in the CD4-induced coreceptor binding domain of gp120 were poorly accessible and were difficult to induce and stabilize with soluble CD4 on Env-pseudotyped viruses. These results illustrate key genetic and antigenic properties of subtype C HIV-1 that might impact the design and testing of candidate vaccines. A subset of these gp160 clones are suitable for use as reference reagents to facilitate standardized assessments of vaccine-elicited neutralizing antibody responses.

Gene Products, env↗

PubMed2006

Single epitope mucosal vaccine delivered via immuno-stimulating complexes induces low level of immunity against simian-HIV.

The difficulty in developing an effective vaccine to contain the HIV/AIDS epidemic coupled with the fact that primary HIV-1 infection typically occurs via mucosal sites has increased emphasis on vaccine approaches that protect at mucosal surfaces. In this study we employed HIV and simian-HIV (SHIV)-derived T helper (Th) and cytotoxic T lymphocyte (CTL) single epitopes incorporated into immuno-stimulating complexes (ISCOM) as a candidate immunogens. Immunized rhesus macaques (Macaca mulatta) were challenged with CCR5-tropic SHIV(SF162p4). On the day of challenge, low levels of virus-neutralizing antibodies (Ab) and CTLs were detected in ISCOM-immunized macaques. Greater than 10(5) viral RNA copies per ml of plasma in 2/5 immunized and 3/4 control macaques were detected within 3 weeks post-challenge. Depletion of CD4+ T cells from gut-associated lymphoid tissues (GALT) was observed by post-challenge day (PCD) 14 in all macaques regardless immunization. Nonetheless, lower viral loads and relatively better preservation of peripheral CD4+ T cells following the SHIV infection was observed in ISCOM-immunized macaques. We predict that if coadministered with additional epitopes and/or more efficacious mucosal delivery system or route, HIV/SIV-derived peptide vaccines may have potential to elicit heterologous protection.

Adjuvants, Immunologic↗

PubMed2006

Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys.

Vaccine-induced cellular immunity controls virus replication in simian immunodeficiency virus (SIV)-infected monkeys only transiently, leading to the question of whether such vaccines for AIDS will be effective. We immunized monkeys with plasmid DNA and replication-defective adenoviral vectors encoding SIV proteins and then challenged them with pathogenic SIV. Although these monkeys demonstrated a reduction in viremia restricted to the early phase of SIV infection, they showed a prolonged survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates of vaccine efficacy should guide the evaluation of AIDS vaccines in humans.

Amino Acid Sequence↗

PubMed2006

Studies on GM-CSF DNA as an adjuvant for neutralizing Ab elicited by a DNA/MVA immunodeficiency virus vaccine.

Here, we use a vaccine consisting of DNA priming followed by MVA boosting in rhesus macaques to investigate the ability of GM-CSF DNA to serve as an adjuvant for the elicitation of neutralizing Ab against an HIV-1 Env. The trial used Gag, Pol, and Env sequences from SHIV-89.6 in the immunogens and a neutralization escape variant of SHIV-89.6, SHIV-89.6P, for challenge. Co-delivery of GM-CSF and vaccine DNAs enhanced the temporal appearance of neutralizing Ab and broadened the specificity of the neutralizing activity to include SHIV-89.6P. Two long-term SHIV-89.6 infections elicited neutralizing activity for SHIV-89.6 but not SHIV-89.6P. Studies on the avidity of the anti-Env antisera revealed that the GM-CSF-adjuvanted vaccine had elicited higher avidity Ab than the non-adjuvanted vaccine or the infection. The GM-CSF-adjuvanted group showed a trend towards better control of the challenge infection and had better control of re-emergent virus (P < 0.01) than the non-adjuvanted group.

AIDS Vaccines↗

PubMed2006

Short communication: characteristics of effective immune control of simian/human immunodeficiency virus in pigtail macaques.

Considerable evidence suggests both HIV-specific T cells and neutralizing antibodies (nAb) can, separately, assist control of viremia. T cell and nAb responses were studied in detail in three pigtail macaques protected from chronic simian/human immunodeficiency virus (SHIV) viremia by DNA prime/fowlpoxvirus boost vaccine regimens. Immunity was studied both after an initial intrarectal SHIV challenge, as well as during CD8 T cell depletion and a subsequent intravenous SHIV rechallenge. Remarkably, SHIV-specific CD4 and CD8 T cells were detectable in the absence of viremia following an initial SHIV challenge in one animal, subsequent to recovery from CD8 T cell depletion in all three animals, and following control of heterologous SHIV rechallenge in two animals. Neutralizing antibodies were also enhanced following CD8 depletion without recrudescence of viremia in all three animals. These observations, although in a small subset of animals, suggest the hypothesis that combinations of primed T cell immunity and neutralizing antibodies can maintain control of chronic primate lentiviral infections.

Animals↗

PubMed2006

Comparative evaluation of simian, simian-human, and human immunodeficiency virus infections in the pigtail macaque (Macaca nemestrina) model.

The global impact of HIV/AIDS intensifies the need for a preventive vaccine and nonhuman primate models can help provide critical insights into effective immunity. Pigtail macaques (Macaca nemestrina) are increasingly studied as a nonhuman primate model for AIDS. We compared the virologic and immunologic characteristics of HIV-1, SIV, and SHIV infection of naive pigtail macaques across a series of preclinical HIV vaccine studies. SIVmac251 and SIVmac239 infection of naive pigtail macaques resulted in a gradual decline in peripheral CD4+ T cells in the setting of high levels of viremia, approximating most closely human infection of HIV-1. In contrast, the CXCR4-utilizing SHIVmn229 virus resulted in rapid depletion of CD4+ T cells and minimal generation of humoral or cellular immune responses, similar to that observed with SHIV89.6P infection of rhesus macaques. Infection with the CCR5-utilizing, rhesus macaque passaged, SHIVSF162P3 resulted in some overall CD4+ T cell decline, however, three of eight macaques naturally control SHIVSF162P3 viremia to very low levels in the setting of robust adaptive immunity. Despite attempts at infecting pigtail macaques with HIV-1 strains passaged in juvenile pigtail macaques in vivo or in PBMC isolated from pigtail macaques in vitro, only lower nonsustained levels of viral replication were observed. Our results provide a series of virologic models with which to evaluate potential AIDS vaccines in pigtail macaques.

Animals↗

PubMed2006

Structured treatment interruptions with tenofovir monotherapy for simian immunodeficiency virus-infected newborn macaques.

We demonstrated previously that prolonged tenofovir treatment of infant macaques, starting early during infection with virulent simian immunodeficiency virus (SIVmac251), can lead to persistently low or undetectable viremia even after the emergence of mutants with reduced in vitro susceptibility to tenofovir as a result of a K65R mutation in reverse transcriptase; this control of viremia was demonstrated to be mediated by the generation of effective antiviral immune responses. To determine whether structured treatment interruptions (STI) can induce similar immunologic control of viremia, eight newborn macaques were infected with highly virulent SIVmac251 and started on a tenofovir STI regimen 5 days later. Treatment was withdrawn permanently at 33 weeks of age. All animals receiving STI fared much better than 22 untreated SIVmac251-infected infant macaques. However, there was a high variability among animals in the viral RNA set point after complete drug withdrawal, and none of the animals was able to achieve long-term immunologic suppression of viremia to persistently low levels. Early immunologic and viral markers in blood (including the detection of the K65R mutation) were not predictive of the viral RNA set point after drug withdrawal. These results, which reflect the complex interactions between drug resistance mutations, viral virulence, and drug- and immune-mediated inhibition of virus replication, highlight the difficulties associated with trying to develop STI regimens with predictable efficacy for clinical practice.

Adenine↗

PubMed2006

Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian-human immunodeficiency virus SHIVKU2 RNA levels.

Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIV(KU2) (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques.

AIDS Vaccines↗

PubMed2006

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates.

Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1.

AIDS Vaccines↗

PubMed2006

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates.

AIDS Vaccines↗

PubMed2005

Analysis of HIV-1 subtype B third variable region peptide motifs for induction of neutralizing antibodies against HIV-1 primary isolates.

The HIV-1 gp120 V3 loop is a potent inducer of neutralizing antibodies for T cell line adapted-HIV-1, but less so for primary isolates. We hypothesized that peptides representative of the diversity of natural HIV-1 V3 loop variants might capture elements of conserved higher order structures and so stimulate broadly reactive neutralizing antibodies. We designed a panel of 29 subtype B V3 sequences postulated to reflect the range of V3 diversity. These peptides were used to immunize guinea pigs. The most effective peptide (62.19) clustered around the subtype B consensus sequence and induced antibodies that reproducibly neutralized 31% of the subtype B HIV-1 primary isolates evaluated, but exhibited limited cross-neutralization of non-subtype B HIV-1 strains. Taken together, these data demonstrated that the limited neutralization profile of antibodies induced by optimal subtype B V3 motifs likely represents the maximum breadth of neutralization of subtype B HIV-1 primary isolates attainable by anti-V3 peptide antibodies.

Amino Acid Motifs↗