Live-virus exposure of vaccine-protected macaques alters the anti-HIV-1 antibody repertoire in the absence of viremia.

BACKGROUND: We addressed the question whether live-virus challenges could alter vaccine-induced antibody (Ab) responses in vaccinated rhesus macaques (RMs) that completely resisted repeated exposures to R5-tropic simian-human immunodeficiency viruses encoding heterologous HIV clade C envelopes (SHIV-Cs). RESULTS: We examined the Ab responses in aviremic RMs that had been immunized with a multi-component protein vaccine (multimeric HIV-1 gp160, HIV-1 Tat and SIV Gag-Pol particles) and compared anti-Env plasma Ab titers before and after repeated live-virus exposures. Although no viremia was ever detected in these animals, they showed significant increases in anti-gp140 Ab titers after they had encountered live SHIVs. When we investigated the dynamics of anti-Env Ab titers during the immunization and challenge phases further, we detected the expected, vaccine-induced increases of Ab responses about two weeks after the last protein immunization. Remarkably, these titers kept rising during the repeated virus challenges, although no viremia resulted. In contrast, in vaccinated RMs that were not exposed to virus, anti-gp140 Ab titers declined after the peak seen two weeks after the last immunization. These data suggest boosting of pre-existing, vaccine-induced Ab responses as a consequence of repeated live-virus exposures. Next, we screened polyclonal plasma samples from two of the completely protected vaccinees by peptide phage display and designed a strategy that selects for recombinant phages recognized only by Abs present after - but not before - any SHIV challenge. With this "subtractive biopanning" approach, we isolated V3 mimotopes that were only recognized after the animals had been exposed to live virus. By detailed epitope mapping of such anti-V3 Ab responses, we showed that the challenges not only boosted pre-existing binding and neutralizing Ab titers, but also induced Abs targeting neo-antigens presented by the heterologous challenge virus. CONCLUSIONS: Anti-Env Ab responses induced by recombinant protein vaccination were altered by the multiple, live SHIV challenges in vaccinees that had no detectable viral loads. These data may have implications for the interpretation of "vaccine only" responses in clinical vaccine trials.

Rhesus macaques vaccinated with consensus envelopes elicit partially protective immune responses against SHIV SF162p4 challenge.

The development of a preventative HIV/AIDS vaccine is challenging due to the diversity of viral genome sequences, especially in the viral envelope (Env160). Since it is not possible to directly match the vaccine strain to the vast number of circulating HIV-1 strains, it is necessary to develop an HIV-1 vaccine that can protect against a heterologous viral challenge. Previous studies from our group demonstrated that a mixture of wild type clade B Env(gp160s) were able to protect against a heterologous clade B challenge more effectively than a consensus clade B Envg(p160) vaccine. In order to broaden the immune response to other clades of HIV, in this study rhesus macaques were vaccinated with a polyvalent mixture of purified HIV-1 trimerized consensus Envg(p140) proteins representing clades A, B, C, and E. The elicited immune responses were compared to a single consensus Env(gp140) representing all isolates in group M (Con M). Both vaccines elicited anti- Env(gp140) IgG antibodies that bound an equal number of HIV-1 Env(gp160) proteins representing clades A, B and C. In addition, both vaccines elicited antibodies that neutralized the HIV-1(SF162) isolate. However, the vaccinated monkeys were not protected against SHIV(SF162p4) challenge. These results indicate that consensus Env(gp160) vaccines, administered as purified Env(gp140) trimers, elicit antibodies that bind to Env(gp160s) from strains representing multiple clades of HIV-1, but these vaccines did not protect against heterologous SHIV challenge.

Induction of Neutralizing Responses against Autologous Virus in Maternal HIV Vaccine Trials.

A maternal vaccine capable of boosting neutralizing antibody (NAb) responses directed against circulating viruses in HIV-infected pregnant women could effectively decrease mother-to-child transmission of HIV. However, it is not known if an HIV envelope (Env) vaccine administered to infected pregnant women could enhance autologous virus neutralization and thereby reduce this risk of vertical HIV transmission. Here, we assessed autologous virus NAb responses in maternal plasma samples obtained from AIDS Vaccine Evaluation Group (AVEG) protocols 104 and 102, representing historical phase I safety and immunogenicity trials of recombinant HIV Env subunit vaccines administered to HIV-infected pregnant women (ClinicalTrials registration no. NCT00001041). Maternal HIV Env-specific plasma binding and neutralizing antibody responses were characterized before and after vaccination in 15 AVEG 104 (n = 10 vaccine recipients, n = 5 placebo recipients) and 2 AVEG 102 (n = 1 vaccine recipient, n = 1 placebo recipient) participants. Single-genome amplification (SGA) was used to obtain HIV env gene sequences of autologous maternal viruses for pseudovirus production and neutralization sensitivity testing in pre- and postvaccination plasma of HIV-infected pregnant vaccine recipients (n = 6 gp120, n = 1 gp160) and placebo recipients (n = 3). We detected an increase in Env subunit MN gp120-specific IgG binding in the group of vaccine recipients between the first immunization visit and the last visit at delivery (P = 0.027, 2-sided Wilcoxon test). While no difference was observed in the levels of autologous virus neutralization potency between groups, in both groups maternal plasma collected at delivery more effectively neutralized autologous viruses from early pregnancy than late pregnancy. Immunization strategies capable of further enhancing these autologous virus NAb responses in pregnant women will be important to block vertical transmission of HIV.IMPORTANCE Maternal antiretroviral therapy (ART) has effectively reduced but not eliminated the burden of mother-to-child transmission of HIV across the globe, as an estimated 160,000 children were newly infected with HIV in 2018. Thus, additional preventive strategies beyond ART will be required to close the remaining gap and end the pediatric HIV epidemic. A maternal active immunization strategy that synergizes with maternal ART could further reduce infant HIV infections. In this study, we found that two historic HIV Env vaccines did not enhance the ability of HIV-infected pregnant women to neutralize autologous viruses. Therefore, next-generation maternal HIV vaccine candidates must employ alternate approaches to achieve potent neutralizing antibody and perhaps nonneutralizing antibody responses to effectively impede vertical virus transmission. Moreover, these approaches must reflect the broad diversity of HIV strains and widespread availability of ART worldwide.

Strategies for inducing effective neutralizing antibody responses against HIV-1.

Introduction: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs), which are capable of neutralizing most HIV-1 strains. All bNAbs target the HIV-1 envelope glycoprotein (Env), but Env immunizations usually only induce neutralizing antibodies (NAbs) against the sequence-matched virus and not against other strains.Areas covered: We describe the different strategies that have been explored to improve the breadth and potency of anti-HIV-1 NAb responses. The discussed strategies include the application of engineered Env immunogens, optimization of (bNAb) epitopes, different cocktail and sequential vaccination strategies, nanoparticles and nucleic acid-based vaccines.Expert opinion: A combination of the strategies described in this review and future approaches are probably needed to develop an effective HIV-1 vaccine that can induce broad, potent and long-lasting NAb responses.

Comparison of Antibody Responses Induced by RV144, VAX003, and VAX004 Vaccination Regimens.

The RV144 prime-boost regimen demonstrated efficacy against HIV acquisition while VAX003 and VAX004 did not. Although these trials differed by risk groups, immunization regimens, and immunogens, antibody responses may have contributed to the differences observed in vaccine efficacy. We assessed HIV-specific IgG, both total and subclass, and IgA binding to HIV envelope (Env): gp120 proteins and Cyclic V2 (CycV2) and CycV3 peptides and gp70 V1 V2 scaffolds in these 3 HIV vaccine trials. After two protein immunizations, IgG responses to 92TH023 gp120 (contained in ALVAC-HIV vaccine) were significantly higher in RV144 but responses to other Env were higher in the VAX trials lacking ALVAC-HIV. IgG responses declined significantly between vaccinations. All trials induced antibodies to gp70 V1 V2 but VAX004 responses to 92TH023 gp70 V1 V2 were weak. All CycV2 responses were undetectable in VAX004 while 92TH023 gp70 V1 V2 was detected in both RV144 and VAX003 but MN CycV2 was detected only in VAX003. Multiple protein vaccinations in VAX trials did not improve magnitude or durability of V1 V2 and CycV2 antibodies. Herpes simplex virus glycoprotein D (gD) peptide at the N terminus of AIDSVAX® B/E and B/B gp120 proteins induced antibodies in all trials, although significantly higher in VAX trials. gD peptide induced IgA, IgG1, IgG2, and IgG3 but not IgG4. Multiple protein vaccinations decreased IgG3 and increased IgG4 changing subclass contribution to total IgG. Although confounded by different modes of HIV transmission, higher Env-specific IgA and IgG4 binding antibodies induced in the VAX trials compared to RV144 raises the hypothesis that these differences may have contributed to different vaccine efficacy results.

Immune activation and paediatric HIV-1 disease outcome.

PURPOSE OF REVIEW: The paediatric HIV epidemic is changing. Over the past decade, new infections have substantially reduced, whereas access to antiretroviral therapy (ART) has increased. Overall this success means that numbers of children living with HIV are climbing. In addition, the problems observed in adult infection resulting from chronic inflammation triggered by persistent immune activation even following ART mediated suppression of viral replication are magnified in children infected from birth. RECENT FINDINGS: Features of immune ontogeny favour low immune activation in early life, whereas specific aspects of paediatric HIV infection tend to increase it. A subset of ART-naïve nonprogressing children exists in whom normal CD4 cell counts are maintained in the setting of persistent high viremia and yet in the context of low immune activation. This sooty mangabey-like phenotype contrasts with nonprogressing adult infection which is characterized by the expression of protective HLA class I molecules and low viral load. The particular factors contributing to raised or lowered immune activation in paediatric infection, which ultimately influence disease outcome, are discussed. SUMMARY: Novel strategies to circumvent the unwanted long-term consequences of HIV infection may be possible in children in whom natural immune ontogeny in early life militates against immune activation. Defining the mechanisms underlying low immune activation in natural HIV infection would have applications beyond paediatric HIV.

Seroconversion following nonoccupational postexposure prophylaxis against HIV.

BACKGROUND: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. CONCLUSIONS: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

Designing synthetic vaccines for HIV.

Despite three decades of intensive research efforts, the development of an effective prophylactic vaccine against HIV remains an unrealized goal in the global campaign to contain the HIV/AIDS pandemic. Recent characterization of novel epitopes for inducing broadly neutralizing antibodies has fueled research in the design and synthesis of new, well-defined antigenic constructs for the development of HIV envelope-directed vaccines. The present review will cover previous and recent efforts toward the design of synthetic vaccines based on the HIV viral envelope glycoproteins, with special emphasis on examples from our own laboratories. The biological evaluation of some of the most representative vaccine candidates, in terms of their antigenicity and immunogenicity, will also be discussed to illustrate the current state-of-the-art toward the development of fully synthetic HIV vaccines.

Prevention of HIV transmission by blood transfusion in the developing world: achievements and continuing challenges.

In industrialized countries, the use of sensitive HIV screening tests, donor deferral, and more conservative use of blood have resulted in a dramatic decrease in the transmission of HIV infection by blood transfusion. The risk of HIV transmission in the USA by blood screened negative for HIV antibody was recently estimated at one in 440,000-660,000 donations. Despite this low risk, continued public concern has compelled blood collection agencies and policy makers to continue to search for more sensitive HIV screening tests. Genome amplification techniques are receiving increased attention and are being piloted in Germany. HIV-1 p24 antigen testing was implemented in the USA in March 1996. In the first 18 months of p24 antigen testing, an estimated 18 million blood donations were tested at a cost of US$90 million to detect three antigen-positive, antibody-negative donations. However, in many developing countries where severe anemia is widespread and the prevalence of HIV infection among blood donors is orders of magnitude greater than in industrialized countries, the blood supply is either incompletely screened or not screened at all for HIV antibody. Although the contribution of transfusion-transmitted infection to the HIV epidemic has not been accurately assessed, an estimated 5-10% of HIV infections in developing countries are due to blood transfusion. In a study conducted 1 year after implementation of HIV blood screening in the largest hospital in the capital city of the Democratic Republic of the Congo, an estimated 25% of pediatric HIV infections, and 40% of infections among children over 1 years of age, were due to transfusion. Lack of commitment by national governments and international aid organizations to this fundamental element of HIV prevention has resulted in a shortage of basic equipment, supplies, and trained personnel for blood screening. Moreover, provision of test kits alone cannot prevent HIV transmission by transfusion in resource-poor areas. More comprehensive programs are needed to improve the recruitment and retention of safe donors, essential laboratory services for blood banking and screening, technical training and supervision, appropriate use of transfusions, and the prevention of severe anemia. This article summarizes the steps being taken by developing countries to prevent HIV transmission by blood transfusion, lessons learned, and the work that still lies ahead.

PIP: Screening of the blood supply, a cost-effective strategy for reducing HIV transmission, has not been implemented consistently in developing countries. An estimated 5-10% of HIV transmission in these countries remains attributable to blood transfusion. Lack of commitment by national governments and international aid organizations has resulted in a shortage of basic equipment, supplies, and trained personnel for blood screening. The situation is further complicated by problems recruiting and retaining safe donors, a lack of essential laboratory services for blood banking and screening, the nonavailability of rapid tests, inadequate supervision of personnel, and widespread need for blood transfusions for malaria-related severe anemia. International donor organizations, government agencies, and health care providers are urged to give renewed attention to the issue of blood safety in resource-poor areas of the world so that this effective method of HIV prevention can be universally accessible.

Testing for HIV in the public and private sectors--Oregon, 1988-1991.

Counseling and testing persons for human immunodeficiency virus (HIV) infection is a key component of the public health strategy for reducing transmission of HIV in the United States (1,2). In 1991, the federal government allocated $100 million to state and local health agencies to provide counseling and testing programs in public clinics for at-risk persons, including persons who may not otherwise use public health services. However, the relative contribution of HIV-testing in public clinics to HIV testing in the private sector is unknown. To compare HIV testing in Oregon public clinics to overall HIV testing, the Health Division (HD) of the Oregon Department of Human Resources, in cooperation with CDC, reviewed data collected from September 1, 1988, through August 31, 1991, on public and private HIV testing in Oregon. This report summarizes findings for HIV testing rates and assesses the importance of publicly funded testing in identifying HIV-seropositive persons.

High-risk sexual behaviors in a context of substance abuse: a focus group approach.

Clinical studies show that heavy and dependant substance users engage with high frequency in high-risk sexual behaviors. To better understand the dynamics of unsafe sexual practices among alcoholics or non-intravenous drug users (IDUs), a series of focus group discussions was conducted with 26 single, sexually active men and women in treatment for substance abuse. Results show that unsafe sexual practices in this subgroup may be explained by three factors: (1) intoxication, (2) negative perceptions of condoms, and (3) cognitive distortions. Furthermore, men's negative perceptions of condoms and women's concerns about not opposing men by fear of being rejected seem to be synergetic to bringing about the negative outcome. Implications for clinical practices are discussed.

The provision of safe blood--policy issues in the prevention of human immunodeficiency virus transmission.

The AIDS epidemic has focused attention on the constraints and deficiencies present in many blood transfusion services in the developing world. We discuss a variety of options for reducing transfusion-related HIV transmission, and suggest how new transfusion strategies may be implemented. We show that a transfusion service cannot rely solely on the screening of donor blood for anti-HIV antibodies and that a more comprehensive approach is needed. Important components of this approach include donor selection and improved clinical practice, in which blood and blood products are prescribed only when really necessary.

Postexposure prophylaxis for HIV.

AIDS: Postexposure prophylaxis represents an advance in the management of percutaneous exposure to HIV in the workplace, but its efficacy in other settings needs further study. Three types of occupational exposure, percutaneous, mucous membrane, skin contact or loss of skin integrity, the postexposure prophylaxis to be used or offered, and the risk data and assessment for HIV acquisition are examined. Analysis of HIV transmission through percutaneous exposure reveals that occupational risk for health care workers is increased by deep injury to the exposed worker, visible blood on the injuring device, exposure of the device to source patients' vein or artery, and source patient's death from AIDS within 60 days of the accident. Prophylaxis for percutaneous exposure, if indicated, should be initiated within 1 to 2 hours to be effective. HIV antibody titers should be measured immediately and at 6 weeks, 12 weeks, and 6 months after exposure. AZT prophylaxis following percutaneous occupational exposure has dramatically decreased transmission in this setting and multiple drug regimens have become the standard of care to further increase efficacy. Sexual contact is the most frequent means of transmitting HIV infection and reducing exposure is the mainstay of public health efforts. Prophylaxis after non-occupational exposures such as sexual intercourse or sharing needles could potentially decrease transmission, although efficacy has not yet been demonstrated. Routine prophylaxis after sexual exposure may be an ineffective strategy.^ieng

Importance of neutralization sieve analyses when seeking correlates of HIV-1 vaccine efficacy.

This commentary describes a rationale for the use of breakthrough viruses from clinical trial participants to assess neutralizing antibodies as a correlate of HIV-1 vaccine efficacy. The rationale is based on principles of a genetic sieve analysis, where the 2 analyses may be cooperative for delineating neutralizing antibodies as a mechanistic correlate of protection.

Will studies in individuals with systemic lupus erythematosus be the key to future HIV vaccine design?

The induction of HIV-1 broadly neutralizing antibodies (bnAbs) remains the primary goal of a preventive HIV-1 vaccine but no HIV-1 vaccine candidate has succeeded in inducing bnAbs. All the bnAbs isolated from chronically HIV-1 infected subjects display one or more traits associated with control by host tolerance and immunoregulatory mechanisms, including reactivity against self antigens. Recent studies on a HIV-1 patient with concurrent systemic lupus erythematosus have informed on how similar bnAbs are to typical autoantibodies controlled by immune tolerance mechanisms. Future studies aimed at elucidating the intersection between autoantibodies generated in the context of systemic lupus erythematosus and the development of HIV-1 bnAbs will further our knowledge of specific roadblocks that hamper the production of bnAbs and, ultimately, inform us on how to implement vaccine strategies to circumvent them.

[The management of dialysis patients seropositive for HBsAg, anti-HCV, or anti-HIV antibodies]. / La gestione del paziente HBsAg positivo, HCV positivo e HIV positivo in dialisi.

Infections by hepatitis B or hepatitis C virus are still common among patients on maintenance dialysis in Western countries. The natural history of HBV and HCV in the dialysis population remains unclear; however, there is good evidence showing an adverse impact of an anti-HCV seropositive status on survival in dialysis patients. A recent meta-analysis of observational studies (n=7, 11,589 unique patients) reported that anti-HCV-positive patients on dialysis had a higher mortality rate than those who were anti-HCV negative (adjusted hazard ratio=1.35, 95% confidence interval, 1.13; 1.59, p<0.001). This was in part attributed to a higher frequency of chronic hepatitis C and its attending complications (cirrhosis and hepatocellular carcinoma). In addition, HCV appeared to have a negative influence on quality of life. Recent clinical guidelines by the KDIGO Study Group have not suggested the isolation of anti-HCV-positive patients on maintenance dialysis. Standard precautions and specific procedures against the transmission of blood-borne agents have been recommended to control HCV infection within dialysis units. Isolation by dialysis machines, staff and rooms has been strongly recommended to control HBV. Vaccination is an important tool against transmission of HBV infection among patients on maintenance dialysis; however, the immune response towards the hepatitis B vaccine in uremic patients remains unsatisfactory. Monotherapy with lamivudine is currently used for dialysis patients with hepatitis B whereas combination antiviral therapy (pegylated interferon plus ribavirin) is the standard of care for hepatitis C in the dialysis population, even if various side effects have been observed.

Perinatally human immunodeficiency virus-1 infected children born to low risk mothers who tested antibody negative during pregnancy: three cases.

Current Centers for Disease Control and Prevention (CDC) recommendations suggest all pregnant women have human immunodeficiency virus (HIV) antibody testing early in pregnancy. For women with specific identified risks for HIV-1 infection, the CDC recommends repeat testing in the third trimester. We report 3 cases of infants perinatally infected with HIV-1 whose mothers tested negative for HIV-1 during the first trimester of pregnancy. Because they were not considered to be "high risk" for HIV-1 infection, they did not have a third trimester HIV test. These cases suggest that repeat HIV antibody testing may be necessary to avoid cases of perinatal transmission that might be prevented with antiretroviral treatment during pregnancy.