Prevent Human Immunodeficiency Virus Type 1 Infection Research Articles

Surface-Functionalized Silica-Coated Calcium Phosphate Nanoparticles Efficiently Deliver DNA-Based HIV-1 Trimeric Envelope Vaccines against HIV-1.

Human immunodeficiency virus type 1 (HIV-1) infection remains one of the worst crises in global health. The prevention of HIV-1 infection is a crucial task that needs to be addressed due to the absence of a licensed vaccine against HIV-1. DNA vaccines present a promising alternative approach to combat HIV-1 infection due to their excellent safety profile, lack of severe side effects, and relatively rapid fabrication. Traditional vaccines composed of a monomeric envelope or peptide fragments have been indicated to lack protective efficacy mediated by inducing HIV-1-specific neutralizing antibodies in clinical trials. The immunogenicity and protection against HIV-1 induced by DNA vaccines are limited due to the poor uptake of these vaccines by antigen-presenting cells and their ready degradation by DNases and lysosomes. To address these issues of naked DNA vaccines, we described the feasibility of CpG-functionalized silica-coated calcium phosphate nanoparticles (SCPs) for efficiently delivering DNA-based HIV-1 trimeric envelope vaccines against HIV-1. Vaccines comprising the soluble BG505 SOSIP.664 trimer fused to the GCN4-based isoleucine zipper or bacteriophage T4 fibritin foldon motif with excellent simulation of the native HIV-1 envelope were chosen as trimer-based vaccine platforms. Our results showed that SCP-based DNA immunization could significantly induce both broad humoral immune responses and potent cellular immune responses compared to naked DNA vaccination in vivo. To the best of our knowledge, this study is the first to assess the feasibility of CpG-functionalized SCPs for efficiently delivering DNA vaccines expressing a native-like HIV-1 trimer. These CpG-functionalized SCPs for delivering DNA-based HIV-1 trimeric envelope vaccines may lead to the development of promising vaccine candidates against HIV-1.

Islatravir for the treatment and prevention of infection with the human immunodeficiency virus type 1.

To discuss the potential role of islatravir (ISL), a novel reverse transcriptase translocation inhibitor, in the treatment and prevention of human immunodeficiency virus type 1 (HIV-1) infection. Islatravir (4'-ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591) is a long-acting first-in-class nucleoside reverse transcriptase translocation inhibitor with the potential for versatile dosing routes and dosing intervals. It demonstrated robust antiviral activity when dosed once daily and once weekly in HIV-1-infected individuals and SIV-infected rhesus macaques. In clinical trials of ISL in combination with doravirine and lamivudine, daily oral administration resulted in high levels of virologic suppression in HIV-infected individuals. In preclinical studies, ISL dosed orally once-weekly as preexposure prophylaxis (PrEP), protected rhesus macaques against SHIV infection via the mucosal route in the low-dose rectal challenge model. Most recently, data in healthy HIV-1-uninfected individuals demonstrated the feasibility of formulating of ISL as an implant. In these studies, levels of intracellular ISL-triphosphate were consistent with the potential for a once-yearly implantable administration of ISL as PrEP. Islatravir is a promising new agent for both the treatment and prevention of HIV-1 infection.

Expression, Purification and Characterization of Hiv-1 Capsid Precursor Protein p41.

Human immunodeficiency virus type 1 (HIV-1) has been a global epidemic since 1983; yet, the virology and immunology related to HIV-1 remain elusive. Furthermore, as there is still no effective chemoprophylaxis or vaccine to treat patients with HIV-1, most research focuses on strategies to prevent HIV-1 infection, such as with antiviral drugs, novel therapeutics, or improved diagnostic kits. The HIV-1 Gag precursor protein (p55)-comprising the matrix (MA/p17), capsid (CA/p24), and nucleocapsid (NC/p7) protein domains-is the main structural HIV-1 protein, and is uniquely responsible for virion assembly within the virus life cycle. Recently, the immature and mature capsid structures were solved; however, the precursor protein structure is still unknown. Here, we expressed two subtypes of HIV-1 MA-CA stretch of the Gag protein, referred to as p41, in a bacterial expression system. We characterized the purified p41 protein, and showed its superior antigenicity over that of p24, highlighting the potential influence of the p17 domain on p24 structure. We further showed that p41 has good immunogenicity to induce an antibody response in mice. These results will aid future investigations into the HIV-1 capsid precursor structure, and potentially contribute to improving the design of diagnostic kits.

G2-S16 dendrimer as a candidate for a microbicide to prevent HIV-1 infection in women.

Unprotected heterosexual intercourse is the first route for sustaining the global spread of human immunodeficiency virus type 1 (HIV-1), being responsible for 80% of new HIV-1 infections in the world. The presence of inflammation in the female reproductive tract and the presence of semen increases the risk of heterosexual HIV-1 transmission. This state-of-the-art research based on an innovative nanotechnology design was focused on a toxicological study of the limitation of the activity of the novel H2O-soluble anionic carbosilane dendrimer G2-S16 in the adult cervical and foreskin epithelia. The G2-S16 dendrimer did not cause any irritation or inflammation in the vaginal epithelium, proving that this dendrimer is a safe nanocompound for vaginal application to control viral transmission. It was shown that no significant differences were found in mortality, sublethal or teratogenic effects when the zebra fish embryos were treated with G2-S16. In short, G2-S16 seems to be an ideal candidate for the development of a topical microbicide against HIV-1 infection and the next step is try in clinical trials, because of its great in vivo biocompatibility, as well as its ability to halt HIV-1 infection in the presence of semen.

Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection.

Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 g/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled.

Escherichia coli surface display of single-chain antibody VRC01 against HIV-1 infection

Human immunodeficiency virus type 1 (HIV-1) transmission and infection occur mainly via the mucosal surfaces. The commensal bacteria residing in these surfaces can potentially be employed as a vehicle for delivering inhibitors to prevent HIV-1 infection. In this study, we have employed a bacteria-based strategy to display a broadly neutralizing antibody VRC01, which could potentially be used to prevent HIV-1 infection. The VRC01 antibody mimics CD4-binding to gp120 and has broadly neutralization activities against HIV-1. We have designed a construct that can express the fusion peptide of the scFv-VRC01 antibody together with the autotransporter β-barrel domain of IgAP gene from Neisseria gonorrhoeae, which enabled surface display of the antibody molecule. Our results indicate that the scFv-VRC01 antibody molecule was displayed on the surface of the bacteria as demonstrated by flow cytometry and immunofluorescence microscopy. The engineered bacteria can capture HIV-1 particles via surface-binding and inhibit HIV-1 infection in cell culture.

Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

HSV Neutralization by the Microbicidal Candidate C5A

Genital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to prevent HIV-1 infection but neither influenza nor vesicular stomatitis virus infections. Here we investigated the antiviral function of C5A on HSV infections. C5A efficiently inhibited both HSV-1 and HSV-2 infection in epithelial cells in vitro as well as in an ex vivo epidermal infection model. C5A destabilized the integrity of the viral HSV membrane. Furthermore, drug resistant HSV strains were inhibited by this peptide. Notably, C5A-mediated neutralization of HSV-1 prevented HIV-1 transmission. An in vitro HIV-1 transmigration assay was developed using primary genital epithelial cells and HSV infection increased HIV-1 transmigration. Treatment with C5A abolished HIV-1 transmigration by preventing HSV infection and by preserving the integrity of the genital epithelium that was severely compromised by HSV infection. In conclusion, this study demonstrates that C5A represents a multipurpose microbicide candidate, which neutralizes both HIV-1 and HSV, and which may interfere with HIV-1 transmission through the genital epithelium.

Combinatorial Approaches to the Prevention and Treatment of HIV-1 Infection

The discovery of the human immunodeficiency virus type 1 (HIV-1) in 1982 soon led to the identification and development of antiviral compounds to be used in treatment strategies for infected patients. Early in the epidemic, drug monotherapies frequently led to treatment failures because the virus quickly developed resistance to the single drug. Following the advent of highly active antiretroviral therapy (HAART) in 1995, dramatic improvements in HIV-1-infected patient health and survival were realized as more refined combination therapies resulted in reductions in viral loads and increases in CD4+ T-cell counts. In the absence of an effective vaccine, prevention of HIV-1 infection has also gained traction as an approach to curbing the pandemic. The development of compounds as safe and effective microbicides has intensified and has focused on blocking the transmission of HIV-1 during all forms of sexual intercourse. Initial preclinical investigations and clinical trials of microbicides focused on single compounds effective against HIV-1. However, the remarkable successes achieved using combination therapy to treat systemic HIV-1 infection have subsequently stimulated the study and development of combination microbicides that will simultaneously inhibit multiple aspects of the HIV-1 transmission process by targeting incoming viral particles, virus-infected cells, and cells susceptible to HIV-1 infection. This review focuses on existing and developing combination therapies, covering preclinical development, in vitro and in vivo efficacy studies, and subsequent clinical trials. The shift in focus within the microbicide development field from single compounds to combination approaches is also explored.

Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand

The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P=0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P=0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P=0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

Modulation of Human Immunodeficiency Virus Type 1 Infectivity through Incorporation of Tetraspanin Proteins

Accumulating evidence indicates that human immunodeficiency virus type 1 (HIV-1) acquires various cellular membrane proteins in the lipid bilayer of the viral envelope membrane. Although some virion-incorporated cellular membrane proteins are known to potently affect HIV-1 infectivity, the virological functions of most virion-incorporated membrane proteins remain unclear. Among these host proteins, we found that CD63 was eliminated from the plasma membranes of HIV-1-producing T cells after activation, followed by a decrease in the amount of virion-incorporated CD63, and in contrast, an increase in the infectivity of the released virions. On the other hand, we found that CD63 at the cell surface was preferentially embedded on the membrane of released virions in an HIV-1 envelope protein (Env)-independent manner and that virion-incorporated CD63 had the potential to inhibit HIV-1 Env-mediated infection in a strain-specific manner at the postattachment entry step(s). In addition, these behaviors were commonly observed in other tetraspanin proteins, such as CD9, CD81, CD82, and CD231. However, L6 protein, whose topology is similar to that of tetraspanins but which does not belong to the tetraspanin superfamily, did not have the potential to prevent HIV-1 infection, despite its successful incorporation into the released particles. Taken together, these results suggest that tetraspanin proteins have the unique potential to modulate HIV-1 infectivity through incorporation into released HIV-1 particles, and our findings may provide a clue to undiscovered aspects of HIV-1 entry.

The retrocyclin analogue RC‐101 prevents human immunodeficiency virus type 1 infection of a model human cervicovaginal tissue construct

Retrocyclins are cyclic antimicrobial peptides that exhibit potent activity towards a broad range of primary and laboratory-adapted strains of human immunodeficiency virus type 1 (HIV-1) in vitro. The current study shows that RC-101, an analogue of retrocyclin, prevented HIV-1 infection in an organ-like construct of human cervicovaginal tissue and retained full activity in the presence of vaginal fluid. The peptide remained within the cervicovaginal tissues throughout the 9-day incubation period without altering tissue viability, inducing damage or inducing the release of inflammatory cytokines. Collectively, these data support the potential development of RC-101 as a topical microbicide to prevent HIV-1 infection and transmission.

Randomized, Double‐Blind, Placebo‐Controlled Efficacy Trial of a Bivalent Recombinant Glycoprotein 120 HIV‐1 Vaccine among Injection Drug Users in Bangkok, Thailand

In Thailand, phase 1/2 trials of monovalent subtype B and bivalent subtype B/E (CRF01_AE) recombinant glycoprotein 120 human immunodeficiency virus type 1 (HIV-1) vaccines were successfully conducted from 1995 to 1998, prompting the first HIV-1 vaccine efficacy trial in Asia. This randomized, double-blind, placebo-controlled efficacy trial of AIDSVAX B/E (VaxGen), which included 36-months of follow-up, was conducted among injection drug users (IDUs) in Bangkok, Thailand. The primary end point was HIV-1 infection; secondary end points included plasma HIV-1 load, CD4 cell count, onset of acquired immunodeficiency syndrome-defining conditions, and initiation of antiretroviral therapy. A total of 2546 IDUs were enrolled between March 1999 and August 2000; the median age was 26 years, and 93.4% were men. The overall HIV-1 incidence was 3.4 infections/100 person-years (95% confidence interval [CI], 3.0-3.9 infections/100 person-years), and the cumulative incidence was 8.4%. There were no differences between the vaccine and placebo arms. HIV-1 subtype E (83 vaccine and 81 placebo recipients) accounted for 77% of infections. Vaccine efficacy was estimated at 0.1% (95% CI, -30.8% to 23.8%; P=.99, log-rank test). No statistically significant effects of the vaccine on secondary end points were observed. Despite the successful completion of this efficacy trial, the vaccine did not prevent HIV-1 infection or delay HIV-1 disease progression.

How Can (−)-Epigallocatechin Gallate from Green Tea Prevent HIV-1 Infection? Mechanistic Insights from Computational Modeling and the Implication for Rational Design of Anti-HIV-1 Entry Inhibitors

Possible inhibitors preventing human immunodeficiency virus type 1 (HIV-1) entry into the cells are recognized as hopeful next-generation anti-HIV-1 drugs. It is highly desirable to develop a potent inhibitor blocking binding of glycoprotein CD4 of the cell with glycoprotein gp120 of HIV-1, because the gp120-CD4 binding is the initial step of HIV-1 entry into the cells. It has been recently reported that (-)-epigallocatechin gallate (EGCG) from green tea is an inhibitor blocking gp120-CD4 binding. But the inhibitory mechanism remains unknown. For understanding the inhibitory mechanism, extensive molecular docking, molecular dynamics simulations, and binding free-energy calculations have been performed in this study to predict the most favorable structures of CD4-EGCG, gp120-CD4, and gp120-CD4-EGCG binding complexes in water. The results reveal that EGCG binds with CD4 in such a way that the calculated binding affinity of gp120 with the CD4-EGCG complex is negligible. So, the favorable binding of EGCG with CD4 can effectively block gp120-CD4 binding. The calculated CD4-EGCG binding affinity (DeltaG(bind) = -5.5 kcal/mol, K(d) = 94 microM) is in excellent agreement with available experimental data suggesting IC(50) approximately 100 microM for EGCG-blocking CD4-gp120 binding. These results and insights provide a rational basis for future design of novel, more potent inhibitors to block gp120-CD4 binding.

DNA vaccines against human immunodeficiency virus type 1 in the past decade.

This article reviews advances in the field of human immunodeficiency virus type 1 (HIV-1) and AIDS vaccine development over the last decade, with an emphasis on the DNA vaccination approach. Despite the discovery of HIV-1 and AIDS in humans nearly 20 years ago, there is no vaccine yet that can prevent HIV-1 infection. The focus has shifted toward developing vaccines that can control virus replication and disease progression by eliciting broadly cross-reactive T-cell responses. Among several approaches evaluated, the DNA-based modality has shown considerable promise in terms of its ability to elicit cellular immune responses in primate studies. Of great importance are efforts aimed at improvement of the potency of this modality in the clinic. The review discusses principles of DNA vaccine design and the various mechanisms of plasmid-encoded antigen presentation. The review also outlines current DNA-based vaccine strategies and vectors that have successfully been shown to control virus replication and slow disease progression in animal models. Finally, it lists recent strategies that have been developed as well as novel approaches under consideration to enhance the immunogenicity of plasmid-encoded HIV-1 antigen in various animal models.

Two Mechanisms for Human Immunodeficiency Virus Type 1 Inhibition by N-Terminal Modifications of RANTES

C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.

The potential for heparin and its derivatives in the therapy and prevention of HIV-1 infection.

Heparin is one of several sulphated polysaccharides which potently inhibit replication of the human immunodeficiency virus type 1 (HIV-1) in cultures of CD4+ve human cells. The EC50 value is around 5 microg ml(-1). We have demonstrated that heparin binds to recombinant gp120, the envelope glycoprotein of HIV-1, at a site termed the V3 loop, or principle neutralizing domain, which consists of a disulphide-bridged loop of 32-35 amino acids particularly enriched with basic residues. Using a series of chemically modified heparins we have shown that there is structural specificity in the anti-HIV activity of heparin. Heparin is routinely used clinically as an anticoagulant, and has proved essentially non-toxic and well tolerated. Low anticoagulant derivatives of heparin which retain high anti-HIV-1 activities in vitro may be generated by several routes. Such preparations are ideal candidates for clinical investigation as potential novel therapeutic agents for use in combination with other drugs in the management of AIDS and HIV infection.

Maternal-Fetal Transmission of Human Immunodeficiency Virus.

The World Health Organization estimates that by year 2000, 10 million children will be infected with human immunodeficiency virus type 1 (HIV-1) at birth and will subsequently develop AIDS. Perinatally acquired infections account for the majority of all HIV-1 cases in children, with an estimated mother-to-infant transmission rate of more than 30%. It is not clear why more than half of the children born to HIV-1-infected mothers are uninfected. Maternal transmission of HIV-1 occurs at three levels: prepartum, intrapartum, and postpartum. Several maternal parameters including advanced clinical stages of the mother, low CD4+ lymphocyte counts, maternal immune response to HIV-1, recent infection, high level of circulating HIV-1, and maternal disease progression have been implicated in an increased risk of mother-to-infant transmission of HIV-1. Viral factors influencing mother-to-infant transmission are not known. Furthermore, several other factors such as acute infection during pregnancy, presence of other sexually transmitted diseases (STD) or other chronic infections, vaginal bleeding, disruption of placental integrity, premature rupture of membrane (PROM), and preterm PROM have been associated with mother-to-infant transmission of HIV-1. In addition, tobacco and cigarette smoking during pregnancy have been shown to triple the rate of maternal transmission of HIV-1. The AIDS Clinical Trial Group (ACTG) suggested that zidovudine (ZDV) can reduce therate of mother-to-infant transmission of HIV-1 if administered to HIV-1-infected pregnant women with CD4 counts greater than 200. Moreover, this study failed to take into consideration several factors that may influence maternal transmission of HIV-1. However, the molecular mechanisms involved in mother-to-infant transmission of HIV-1 are not understood, which makes it more difficult to define strategies for effective treatment and prevention of HIV-1 infection in children. Several groups are engaged in the understanding of the molecular and biological properties of HIV-1 influencing mother-to-infant transmission. Results from my and several other laboratories suggest that the minor genotypes, subtypes, or variants of HIV-1 found in a genetically heterogeneous virus population of infected mothers are transmitted to their infants. The minor HIV-1 genotype predominates initially as a homogeneous population in the infant and then becomes diverse as the infant matures. Furthermore, transmission of a major or multiple HIV-1 genotypes from mother to infant has been reported. Taken together, these results strongly suggest that there are differences among the molecular and biological properties of the maternal variants that are transmitted to the infants and the maternal variants that are not transmitted to the infants. The understanding of the molecular and biological properties of the transmitted viruses will enable researchers to target a particular subtype in the mothers that is transmitted to the infants. Copyright 1996 S. Karger AG, Basel

Multibranched peptide constructs derived from the V3 loop of envelope glycoprotein gp120 inhibit human immunodeficiency virus type 1 infection through interaction with CD4

The V3 loop of the gp120 of human immunodeficiency virus type 1 (HIV-1) is assumed to be involved in HIV-1-mediated membrane fusion. V3-derived peptides have been shown either to enhance or to prevent HIV-1 infection. Multibranched peptide constructs (MBPCs) derived from the V3 North American/European consensus sequence were designed to sort out these conflicting findings. At 5 μM, MBPC1 (8-branched GPGRAF) totally, and MBPC2 ([RKSIHIGPGRAFYT]4) partially, inhibited HIV-1 LAI infection, whereas the GPGRAF monomer had only a limited effect. A peptide of the entire V3 consensus loop and a control MBPC had no detectable activity. The 5 μM MBPC1 HIV-1-inhibiting concentration was not cytotoxic, nor did it alter T lymphocyte allogeneic, antigen-, or mitogen-induced reactivities, and it was about 5- to 50-fold lower (MBPC2 and MBPC1, respectively) than that resulting in 50% cell death. Analysis of MBPC immunoreactivity showed that MBPC2, but not MBPC1, strongly reacted with human HIV-1 positive sera. Only MBPC2 elicited significant antibody responses in rabbits. The V3-derived MBPCs bound to CD4 + cells, as determined by immunofluorescence analysis. The binding was inhibited either by soluble CD4 or by CD4 monoclonal antibody (mAb) MT151, which recognizes the CDR3 region of the D1 domain of CD4, but not by other CD4 mAbs Leu3a, OKT4A, Q4021, 13B8-2, 5A8, RFT4, nor by the CD26 mAb BA5. Therefore, it appears likely that MBPCs inhibit HIV-1 infection by interacting with the CDR3 region of CD4 or with a region in its vicinity.