Neutralizing activity and cellular immune responses induced in mice after immunization with apoptotic HIV-1/murine leukemia virus infected cells

Dendritic cells present microbial antigens to T cells after uptake of apoptotic vesicles from infected cells. We previously reported that immunizations with apoptotic HIV-1/murine leukemia virus (MuLV) infected cells lead to induction of both cellular and humoral immune responses as well as resistance to mucosal challenge with live HIV-1/MuLV infected cells. Here we extended those studies and investigated whether apoptotic cells from HIV-1/MuLV infected cells stimulate the production of HIV-1 neutralizing activity.We compared different routes of administration and were able to induce p24- and Nef-specific cellular proliferation after intraperitoneal (i.p.), intranasal (i.n.), subcutaneous (s.c.) and intramuscular (i.m.) immunizations. Serum IgG and IgA antibodies directed against gp160, p24, or Nef were also produced regardless of immunization route used. However, the induction of mucosa-associated IgAs from faeces or vaginal secretions were detected only after either i.p. or i.n. immunizations. We were able to measure neutralizing activity in sera of mice after i.p. and i.n. immunization. Neutralizing reactivity was also detected after s.c. and i.m. immunizations in the presence of the cytokine adjuvant granulocyte macrophage-colony stimulating factor (GM-CSF).Conclusively we show induction of cellular and humoral immune responses including neutralizing activity after immunization with apoptotic HIV-1/MuLV infected cells in mice. The results from this study support further evaluations using apoptotic cells as antigen delivery system for vaccination against HIV-1 in other animal models.     

Antibody but not memory B-cell responses are tuned-down in vertically HIV-1 infected children and young individuals being vaccinated yearly against influenza

Yearly immunization against seasonal influenza is highly recommended for HIV-1 infected individuals but evaluating the success of vaccination by serological markers may not be fully informative in this population. Recently, it has been hypothesized that the generation of long-lasting immune responses may depend on whether similar antigens challenge the immune system frequently and intermittently. In the present study, in order to search for additional correlates of vaccine-induced protective immunity and to further dissect this theory, both humoral and memory B-cell responses to the trivalent 2012–2013 seasonal influenza vaccination has been evaluated by strain-specific (separately for H1N1, H3N2 and B strain) standard hemagglutination inhibition (HI) assay and B-cell enzyme-linked immunosorbent spot (ELISpot) in a cohort of vertically HIV-1 infected children and young individuals as compared to age-matched healthy controls. A high number of HIV-1 infected individuals had protective antibody levels prior to vaccination and showed low seroconversion rates after vaccination as compared to healthy controls. On the contrary, similar frequencies of influenza-specific memory B-cells were detected by B-cell ELISpot in both groups suggesting that an adequate B-cell response has been elicited. Data from the H1N1 strain, which is recurrent in seasonal influenza vaccines since 2009, pointed out decreasing antibody but not memory B-cell responses for HIV-1 infected patients being vaccinated for a greater number of years. Further investigations are required to standardize the influenza-specific B-cell ELISpot and to understand whether it could be used routinely as an additional tool to evaluate response to influenza vaccination in immune-compromised individuals being vaccinated yearly.     

Recombinant Modified Vaccinia Ankara (MVA) effectively boosts DNA-primed HIV-specific immune responses in humans despite pre-existing vaccinia immunity

The presence of vector-specific immune responses may hamper the induction of responses to a foreign antigen encoded by the vector. We evaluated the impact of pre-existing immunity to vaccinia virus on the induction of HIV-specific responses after immunization of healthy volunteers with a HIV-1 DNA prime-MVA boost vaccine. Following three priming immunizations with HIV-1 DNA plasmids, the volunteers were boosted with a single injection of recombinant MVA encoding HIV-1 proteins. Pre-existing immunity to vaccinia virus did not reduce the proportion of individuals who responded to HIV-1, but did lower the magnitude of responses. Our results suggest that vaccinia-based vectors can be used to efficiently induce immune responses to vectored HIV-1 antigens, even in individuals with pre-existing immunity to vaccinia virus.     

Relation of activation-induced deaminase (AID) expression with antibody response to A(H1N1)pdm09 vaccination in HIV-1 infected patients

The relevance of CD4+T-cells, viral load and age in the immunological response to influenza infection and vaccination in HIV-1 infected individuals has previously been pointed out. Our study aimed at assessing, in the setting of 2009 A(H1N1)pdm09 influenza vaccination, whether quantification of activation-induced deaminase (AID) expression in blood B-cells may provide additional indications for predicting antibody response to vaccination in HIV-1 infected patients with similar CD4+T-cell counts and age. Forty-seven healthy controls, 37 ART-treated and 17 treatment-naïve HIV-1 infected patients were enrolled in the study. Blood was collected prior to A(H1N1)pdm09 vaccination and at 1, 3 and 6 months after vaccination. Antibody titers to A(H1N1)pdm09 vaccine were measured by hemagglutination inhibition (HI) assay while the mRNA expression levels of AID were measured by quantitative real time PCR. Upon B-cell activation in vitro, AID increase correlated to antibody response to the A(H1N1)pdm09 vaccine at 1 month after vaccination in all individuals. In addition, the maximum expression levels of AID were significantly higher in those individuals who still carried protective levels of A(H1N1)pdm09 antibodies after 6 months from vaccination. No correlation was found between CD4+T-cell counts or age at vaccination or HIV-1 viral load and levels of A(H1N1)pdm09 antibodies. Assessing AID expression before vaccination may be an additional useful tool for defining a vaccination strategy in immune-compromised individuals at risk of immunization failure.     

Safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine in HIV-1 infected former drug users

The immunogenicity of 23-valent pneumococcal polysaccharide vaccine was assessed in 57 HIV-1 infected former intravenous drug users and in 20 HIV-1 negative controls. The effect of vaccination on HIV-1 infection was studied in a subgroup of 38 patients, 60% of whom under highly active antiretroviral therapy (HAART). Antibody to capsular polysaccharides from Streptococcus pneumoniae serotypes 3, 4, 6B, 19F, 23 F, and changes in CD4+ count, HIV-1 RNA, proviral DNA and HIV-1 phenotype were measured in pre- and post-vaccination samples.Vaccinations were well-tolerated. The rate of responders was higher (P<0.05) in HIV-1 negative than in HIV-1 infected individuals. No difference in antibody response was found within HIV-1 infected patients stratified according to CD4+ counts. Post-vaccination antibody geometric mean concentrations (GMCs) to the five antigens were higher (P<0.05) than baseline in HIV-1 negative subjects, but not in HIV-1 positive individuals. Those with CD4+ >500 cells/mm(3) showed a significant increase of antibody against type 3 only. Immunisation caused no significant changes in CD4+ counts and in either plasma HIV-1 RNA nor proviral DNA levels. Pneumococcal vaccination does not induce virological or immunological deterioration in HIV infected patients, but the antibody response to a single dose of vaccine is poor.     

Increasing prevalence of HIV-2 and dual HIV-1-2 infections among patients attending various outdoor patient departments in Mumbai (Bombay)

Between 1993-96, a serological study was carried out for differentially identifying HIV-1 and HIV-2 infections among the high risk group persons attending the various outdoor patient departments of BYL Nair Municipal Hospital, Mumbai. This study indicates that although HIV-1 is still the predominant virus among the high risk HIV infected persons in Mumbai, dual HIV-1-2 infections are increasing especially among promiscuous heterosexuals and female commercial sex workers. Increases in HIV-2 infections were observed later than dual HIV-1-2 infections, indicating that it is the HIV-1 infected individuals who through continued high risk behavior got infected by HIV-2.     

Immunofocusing using conformationally constrained V3 peptide immunogens improves HIV-1 neutralization

V3-directed antibodies are present in practically all HIV-1 infected patients and in individuals vaccinated with gp120. The levels of maternal V3-directed antibodies were recently shown to correlate with reduced mother to child transmission, and V3 IgGs were found to be a negative correlate of risk in the RV-144 human trial. mAb directed to the tip of the V3 are capable of broad neutralization of Tier-1 and some Tier-2 viruses. Here we report an immunofocusing approach using conformationally constrained V3 peptides of different lengths. Immunofocusing with short constrained V3 peptides following immunizations with long constrained V3 peptides resulted in sera with improved neutralization of Tier-1B viruses in comparison with immunizations with the long constrained peptide alone. Immunizations only with the short constrained peptide were ineffective. Our results demonstrate that immunofocusing with constrained V3 peptides of different lengths could improve the induction of HIV-1 neutralizing antibodies.     

Therapeutic vaccination with MVA-HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals

Vaccination is currently considered as an additional therapeutic approach to stimulate HIV-specific immune response in subjects that could not naturally control HIV. Ten chronically HIV infected individuals have been vaccinated with a modified vaccinia Ankara (MVA)-HIV-1(LAI)-nef vector in order to assess safety and immunogenicity. No significant adverse effects were observed during the course of vaccination indicating for the first time that the highly attenuated vaccinia-virus vector MVA is safe in HIV-1 infected individuals. We observed a CD4 T-cell response to Nef in the majority of vaccinated chronically HIV infected individuals. In two subjects CD4 T-cell response was directed to previously unidentified Nef epitopes. The strong Nef-specific CD4 T-cell response elicited by MVA-nef vaccination provides a rationale for immunotherapeutic interventions in HIV infected individuals with suppressed CD4 T-cell responses. Moreover, the CD4 T-cell response elicited was comparable with that usually detected in long-term non-progressor (LTNP) suggesting an improvement in the immunological status of the vaccinated subjects. Furthermore, the new putative CD4 epitopes described here hold promise as important tools for epitope-based vaccination.     

The natural history of HIV-1 and HIV-2 infections in adults in Africa: a literature review

About 30 million people in Africa are estimated to be living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), yet data about the natural history of infection on the continent are sparse. We reviewed the literature on the natural history of HIV-1 and HIV-2 infections among African adults. Only one study, conducted in rural Uganda, has reported on survival from the time of HIV-1 seroconversion: the median was 9.8 years, which is similar to that reported in developed countries in the early stages of the epidemic and consistent with the findings from the follow-up of individuals identified by serological testing during community-based prevalence studies from Africa. Progression to symptomatic disease was faster in Uganda than in developed countries, due largely to the high background level of morbidity. Various studies suggest that people infected with HIV-2 survive longer and the course of the disease is possibly more variable than in people infected with HIV-1. However no studies have investigated survival from time of seroconversion among people infected with HIV-2. The majority of patients in hospital in Africa with either HIV-1 or HIV-2 have the clinical features of AIDS just before they die, and many are severely immunosuppressed. This is similar to the situation in developed countries before the introduction of highly active antiretroviral therapy (HAART). Potentially preventable infections are the leading causes of death among individuals infected with HIV-1. Prophylactic regimens and better treatments could have some effect on survival, but major improvements in life expectancy will require HAART.     

HIV-1感染者接种23价肺炎疫苗的效果观察研究

目的 观察HIV-1感染者接种23价肺炎球菌多糖疫苗(23-valent pneumococcal polysaccharide vaccine,PPV23)的效果,评价疫苗接种的安全性、保护效果以及成本效益,为相关政策的制定提供参考。方法 用自行设计的调查问卷,通过电话或者面对面访谈对蓝山县2017—2019年接种过PPV23的145名HIV-1感染者进行调查,收集接种PPV23前后一年内接种者肺炎相关疾病的发生情况、接种疫苗后不良反应、相关疾病诊疗信息及费用情况等。结果 145名HIV-1感染者接种PPV23后,患呼吸道疾病和肺炎的发病率等都低于接种疫苗前(P<0.05),但是CD4⁺T细胞计数没有改变。结论 HIV-1感染者接种PPV23有助于降低HIV-1感染者发生肺部机会性感染,有良好的安全性和经济效益,值得在HIV-1感染人群中推广。     

Booster immunization of HIV-1 negative volunteers with HGP-30 vaccine induces protection against HIV-1 virus challenge in SCID mice

Eleven HIV-1 seronegative subjects previously injected with an HIV-1 p17 synthetic peptide vaccine (HGP-30) were given two booster immunizations to evaluate memory cell responses and the ability to boost cellular and humoral immune responses. Five of 11 subjects showed a significant increase in their antibody titres to HGP-30 or p17 and 6/11 had T-cell proliferation responses to either HGP-30 or p17. HIV-1 virus challenge studies in SCID mice demonstrated that 39 of 50 mice (78%) receiving PBMC from 5 of the HGP-30 immunized subjects were protected from infection with a different strain of HIV-1 compared to 4 of 30 mice (13%) that received PBMC from 3 non-immunized subjects (p < 0.001). These studies show that booster immunizations with HGP-30 vaccine are safe and non-toxic and induce protective cell mediated immune responses.     

Mucosal immunity in mice immunized with HIV-1 peptide conjugated to Brucella abortus

We have previously shown that a V3-loop peptide from HIV-1 envelope conjugated to heat-inactivated Brucella abortus (Ba) (V3-Ba) is capable of inducing antibodies that neutralize HIV-1 and cytotoxic T cells (CTL) that kill HIV-1-infected targets, even in mice that lack CD4(+) T cells. In this paper we show that intranasal (i.n.) immunization elicits neutralizing antibodies and IFNgamma-secreting T cells at mucosal surfaces. This approach may protect individuals from HIV-1 infection and reduce transmission from infected individuals to their sexual partners and offspring.     

Massive outbreak of poliomyelitis caused by type-3 wild poliovirus in Angola in 1999

The largest outbreak of poliomyelitis ever recorded in Africa (1093 cases) occurred from 1 March to 28 May 1999 in Luanda, Angola, and in surrounding areas. The outbreak was caused primarily by a type-3 wild poliovirus, although type-1 wild poliovirus was circulating in the outbreak area at the same time. Infected individuals ranged in age from 2 months to 22 years; 788 individuals (72%) were younger than 3 years. Of the 590 individuals whose vaccination status was known, 23% had received no vaccine and 54% had received fewer than three doses of oral poliovirus vaccine (OPV). The major factors that contributed to this outbreak were as follows: massive displacement of unvaccinated persons to urban settings; low routine OPV coverage; inaccessible populations during the previous three national immunization days (NIDs); and inadequate sanitation. This outbreak indicates the urgent need to improve accessibility to all children during NIDs and the dramatic impact that war can have by displacing persons and impeding access to routine immunizations. The period immediately after an outbreak provides an enhanced opportunity to eradicate poliomyelitis. If continuous access in all districts for acute flaccid paralysis surveillance and supplemental immunizations cannot be assured, the current war in Angola may threaten global poliomyelitis eradication.     

American College of Preventive Medicine practice policy statement: childhood immunizations

Vaccine-preventable diseases were a major cause of mortality and morbidity in the United States in the 20th century. With the advent of immunizations, there have been dramatic rates of decline in these diseases. Clinical studies have shown vaccines to be efficacious and cost effective. Despite the simplification of the immunization schedule, vaccination rates are still suboptimal because of missed opportunities. Although several controversies have arisen about the safety of childhood immunizations, they are yet to be validated. There have been recent concerns about the stability of the infrastructure that supports the U.S. immunization program. Research has established strong evidence that certain interventions can increase vaccination coverage rates. The American College of Preventive Medicine outlines recommendations for childhood immunizations.     

Anti-major histocompatibility complex antibody responses in macaques via intradermal DNA immunizations

In simian immunodeficiency virus (SIV) models, immunization of macaques with uninfected human cells or human major histocompatibility complex (MHC) proteins can induce xenogeneic immune responses which can protect the animals from subsequent SIV challenges. These studies suggest that the induction of anti-MHC immune responses can be a viable vaccine strategy against human immunodeficiency virus type 1 (HIV-1). We have previously shown in mouse studies that DNA immunization with class I and class II MHC-encoding plasmids can elicit both xenogeneic and allogeneic antibody responses against conformationally intact MHC molecules (Vaccine 17 (1999) 2479-92). Here we take these observations one step closer to human applications and report that intradermal needle immunizations of non-human primates with plasmid DNA encoding human MHC alleles can safely elicit xenogeneic anti-MHC antibody responses. Moreover, injecting macaques with DNA encoding a specific macaque allogeneic MHC induced anti-allogeneic MHC antibodies production. These studies show that DNA immunization with MHC-encoding vectors can indeed be used to induce specific anti-human xenogeneic, as well as anti-macaque allogeneic MHC immunity in non-human primates. This strategy could thus be used to mobilize anti-MHC antibody response which may be useful as part of an anti-HIV-1 vaccination approach.     

Phenotypic and functional characteristics of HIV-specific CD8 T cells and gag sequence variability after autologous dendritic cells based therapeutic vaccine

A decrease in HIV-1 specific CD8 T-cell responses associated with a partial control of viral replication occurred in 12 HIV-1-infected patients during autologous dendritic cells vaccination. HIV CD8 T cells were detected in 6/10 patients during immunizations, increasing after HAART discontinuation in 3 of them. Tet+ CD8 cells mainly had an effector phenotype (CD45RA−/+ CCR7− and CD28− and Perf+/−) and maintained IFN-γ release throughout follow-up. By contrast, patients with CD45RA−/+ CCR7+ Perf+ HIV-specific cells showed a decrease in peptide-specific IFN-γ production during vaccinations while levels were recovered when off HAART. No major mutations in either Gag p24 and p17 immunodominant epitopes were observed that might have explained the impaired CD8+ T-cell responses. Taken together, heterogeneity in the maturation status of HIV-specific CD8 T cells may be partially involved in the drop of peptide-specific IFN-γ production during immunizations.     

The role of viral coreceptors and enhanced macrophage tropism in human immunodeficiency virus type 1 disease progression

Despite numerous studies on the impact of viral diversity, human immunodeficiency virus type 1 (HIV-1)-specific immune responses and host factors on disease progression, we still do not have a firm understanding of the long-term pathogenesis of HIV-1 infection. Rapid depletion of CD4+ T-lymphocytes has been associated with a switch in viral coreceptor usage from CCR5 to CXCR4 in approximately 40 to 50% of infected individuals. However, the majority of infected individuals who progress to AIDS harbour only CCR5-dependent (R5) viral strains. The progression of HIV-1 disease is associated with an enhanced tropism of R5 viral strains for monocyte/macrophage lineage cells (enhanced M-tropism). However, the underlying molecular mechanisms contributing to enhanced M-tropism by R5 HIV-1 strains, and how HIV-1 variants with enhanced M-tropism cause CD4+ T-cell depletion in vivo are unknown. This review examines the relationship between viral coreceptor usage, M-tropism, and pathogenicity of HIV-1. We highlight evidence supporting the hypothesis that enhanced M-tropism of R5 HIV-1 results from adaptive viral evolution, resulting in HIV-1 variants that have increased ability to utilise relatively low levels of CCR5 expressed on macrophages, by way of increased CCR5 affinity. The evidence also suggests that these late-emerging, R5 viral strains have reduced sensitivity to entry inhibitors, and increased ability to cause CD4+ T-lymphocyte loss. These variants are likely to impact HIV-1 disease progression, especially in patients who persistently harbour only R5 viral strains.     

Comparison of T cell immune responses induced by vectored HIV vaccines in non-human primates and humans

Following the disappointing outcome of the phase IIb test-of-concept step study in which Merck's adenovirus type 5 (Ad5) HIV-1 clade B gag/pol/nef vaccine failed to demonstrate efficacy in HIV high-risk individuals, an extensive review of the trial and preclinical studies which supported the trial is ongoing. One point of interest is how well preclinical nonhuman primate immunogenicity studies predicted what was observed in humans. Here we compare the HIV-1-specific cellular immune responses elicited in nonhuman primates and human clinical trial subjects to several HIV-1 vaccine candidates. We find that although rhesus macaques are immunologically more responsive to vaccination than humans, the hierarchy in potency of single-modality prime-boost regimens using several vector approaches (adenovirus, DNA, and pox vectors) was well predicted. Vaccine approaches using complex formulations such as novel adjuvants (DNA+CRL1005) or mixed-modality prime-boost (DNA/Ad5; Ad5/ALVAC) did not correlate as well between rhesus macaques and humans. Although the immunogenicity of the vaccines and vaccine regimens evaluated were not all accurately predicted, testing in rhesus macaques generally offers an indispensable tool for ranking the immunological potential of HIV-1 vaccine candidates.     

HIV-specific immunity during structured antiviral drug treatment interruption

The immunologic correlates associated with control of viremia in HIV disease are poorly understood. We hypothesized that structured antiviral drug treatment interruptions could be utilized to better understand the relationship between HIV-specific immunity and viral replication. We thus examined the effects of two 8 weeks antiviral structured treatment interruptions (STIs) in a cohort of HIV-1 chronically infected individuals on highly active antiretroviral treatment (HAART) with (n = 13) and without (n = 12) therapeutic HIV immunizations. In this study, we observed that p24 gag antigen (np24) stimulated MIP-1beta levels and T helper immune responses prior to antiviral drug discontinuation were associated with control of viremia. Stronger and earlier production of gag peptide stimulated gamma interferon was observed in the immunized group during the structured antiviral drug interruptions. These results support the concept that HIV-specific immune responses are associated with control of viremia. Further study of immune-based therapies that enhance HIV-specific immunity is warranted.     

Novel Adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag,Pol, Nef despite the presence of Ad5 immunity

Recombinant Adenovirus serotype 5 (Ad5) vectors have been used as vaccine platforms in numerous animal and human clinical studies. The immune response induced by Ad5 vaccines can be mitigated due to pre-existing Ad5 immunity. We previously reported the use of a novel Ad5 platform to induce cellular immune responses (CMI) against HIV-1 Gag in Ad5 hyper immune mice. Here, the effectiveness of the Ad5 [E1-, E2b-] vaccine platform was evaluated using a triad mixture of HIV-1 Gag, Pol, and Nef as antigenic transgenes. Broad CMI was induced following vaccination with the HIV-1 expressing vectors in Ad5 naïve and Ad5 immunized mice. A mixture of the three vaccines induced CMI against each transgene product even in the presence of hyper Ad5 immunity. These studies revealed that CMI responses to immunization with Ad5 [E1-, E2b-]-gag, Ad5 [E1-, E2b-]-pol or Ad5 [E1-, E2b-]-nef vectors were transgene specific and did not induce CMI responses against irrelevant antigens such as carcinoembryonic antigen (CEA), herpes simplex virus glycoprotein B (HSV), cytomegalovirus (CMV) or influenza virus antigens. We are evaluating this recombinant triad viral vector as an HIV-1 vaccine in a non-human primate model and the data indicate that the vaccine is worthy of clinical evaluation.