A Summary of the Sixth International Workshop on Microbiome in HIV Pathogenesis, Prevention, and Treatment.

In October of 2020, researchers from around the world met online for the sixth annual International Workshop on Microbiome in HIV Pathogenesis, Prevention, and Treatment. New research was presented on the roles of the microbiome on immune response and HIV transmission and pathogenesis and the potential for alterations in the microbiome to decrease transmission and affect comorbidities. This article presents a summary of the findings reported.

A Summary of the Fifth Annual Virology Education HIV Microbiome Workshop.

In October of 2019, researchers and community members from around the world met at the NIH for the fifth annual International Workshop on Microbiome in HIV. New research was presented on the role of the microbiome on chronic inflammation and vaccine design, interactions of genetics, environment, sexual practice and HIV infection with the microbiome and the development and clinical trials of microbiome-based therapeutic approaches intended to decrease the probability of HIV acquisition/transmission or ameliorate sequelae of HIV. The keynote address by Dr.

FDA Public Meeting Report on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implications".

Potential drug interactions with hormonal contraceptives are an important public health concern. A public meeting on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implication" was hosted by the United States Food and Drug Administration (FDA). The meeting endeavored to provide an opportunity for the FDA to seek input from experts on the public health concerns associated with the use of hormonal contraceptives and interacting drugs that might affect efficacy and safety, including pharmacokinetic/pharmacodynamic considerations, in the design of drug interaction studies of hormonal contraceptives for drug development and approaches to translating the results of drug interaction information into informative labeling and communication.

Understanding the Intersection of Young Age, Mucosal Injury, and HIV Susceptibility.

Adolescent boys and girls are disproportionately affected in the current HIV epidemic. Numerous sociobehavioral studies have addressed the indirect drivers surrounding this vulnerability-for example, socioeconomic, geographical locale, and all forms of violence. However, the direct factors that may influence infection, such as the anatomical and physiological maturation of the anogenital tracts of adolescents or the trauma and wound-healing processes of injured mucosal tissue, are understudied and represent a gap within the HIV prevention field.

Role of oral pre-exposure prophylaxis (PrEP) in current and future HIV prevention strategies.

Treatment as prevention is expected to have a major role in reducing HIV incidence, but other prevention interventions will also be required to bring the epidemic under control, particularly among key populations. One or more forms of pre-exposure prophylaxis (PrEP) will likely play a critical role. Oral PrEP with emtricitabine-tenofovir (Truvada®) is currently available in the US and some other countries, but uptake has been slow.

Pharmacokinetics and pharmacodynamics in HIV prevention; current status and future directions: a summary of the DAIDS and BMGF sponsored think tank on pharmacokinetics (PK)/pharmacodynamics (PD) in HIV prevention.

Thirty years after its beginning, the HIV/AIDS epidemic is still raging around the world. According to UNAIDS, in 2011 alone 1.7M deaths were attributable to AIDS, and 2.

Topical microbicides to prevent the transmission of HIV: formulation gaps and challenges.

The efforts of the topical microbicide field to identify a safe and effective topical microbicide were realized in July of 2010 with the reporting of the results of the Centre for the AIDS Programme of Research in South Africa 004 trial. In this trial, a 1% tenofovir gel was found to reduce women's risk for HIV acquisition by 39% compared to placebo. To understand the impact of this trial on future microbicide development, we must view it from the historical perspective of previous phases 2 and 3 clinical trials with detergents and sulfated polyanions.

Outcomes of a National Institute of Allergy and Infectious Diseases Workshop on understanding HIV-exposed but seronegative individuals.

The fascinating conundrum that some individuals who are exposed to HIV in ways that would make viral transmission highly likely, yet are able to remain uninfected, has been appreciated for many years. As early as the late 1980s, reports of such individuals began appearing in the HIV/AIDS literature. Despite the critical importance of understanding possible mechanisms of natural HIV resistance for developing effective prevention strategies, numerous obstacles have prevented this essential area of scientific exploration from moving forward.

Beyond 2010: Gaps, Challenges, and Priorities for the Future of Preclinical HIV Preexposure Prophylaxis (PrEP): Summary of the October 20-21, 2009 Workshop.

Abstract A workshop entitled Beyond 2010: Gaps, Challenges, and Priorities for the Future of Preclinical HIV Pre-Exposure Prophylaxis (PrEP) was sponsored by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), on October 20-21, 2009, in Bethesda, Maryland. The objective of the workshop was to identify the main gaps in current knowledge, challenges, and priorities for the establishment of a PrEP preclinical pipeline and to also provide guidance for future directions of the field and DAIDS activities in this area. This 2-day workshop, through various presentations and breakout group discussions, specifically addressed four main topics that will be critical in identifying and advancing the next generation of PrEP candidates for clinical testing.

Preclinical evaluation of a zinc finger inhibitor targeting lentivirus nucleocapsid protein in SIV-infected monkeys.

There is a continued need to develop inexpensive and effective drugs specific for novel targets of human immunodeficiency virus type 1 (HIV-1). The HIV-1 nucleocapsid p7 (NCp7) protein plays a critical role in early and late stages of the virus life cycle and possesses two highly conserved retroviral zinc fingers that are essential for its function. We have previously shown that zinc finger inhibitors (ZFI) based on the S-acyl 2-mercaptobenzamide thioester (SAMT) chemotype specifically target HIV NCp7 and are effective at reducing levels of infectious virus in an HIV-1-transgenic mouse model.

In vitro preclinical testing of nonoxynol-9 as potential anti-human immunodeficiency virus microbicide: a retrospective analysis of results from five laboratories.

The first product to be clinically evaluated as a microbicide contained the nonionic surfactant nonoxynol-9 (nonylphenoxypolyethoxyethanol; N-9). Many laboratories have used N-9 as a control compound for microbicide assays. However, no published comparisons of the results among laboratories or attempts to establish standardized protocols for preclinical testing of microbicides have been performed.

Potent inhibition of HIV-1 entry by (s4dU)35.

We have previously reported the potent in vitro HIV-1 anti-reverse transcriptase activity of a 35-mer of 4-thio-deoxyuridylate [(s(4)dU)(35)]. In efforts to define its activity in a more physiological system, studies were carried out to determine the stage of viral infection that this compound mediates its anti-viral effect. Results of the studies reported herein show that (s(4)dU)(35) is nontoxic and is capable of inhibiting both single and multi-drug resistant HIV strains (IC(50): 0.

Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp.

Griffithsin (GRFT), a novel anti-HIV protein, was isolated from an aqueous extract of the red alga Griffithsia sp. The 121-amino acid sequence of GRFT has been determined, and biologically active GRFT was subsequently produced by expression of a corresponding DNA sequence in Escherichia coli. Both native and recombinant GRFT displayed potent antiviral activity against laboratory strains and primary isolates of T- and M- tropic HIV-1 with EC50 values ranging from 0.

Optimization of unique, uncharged thioesters as inhibitors of HIV replication.

A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercaptobenzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human serum using a spectrophotometric assay.

The next generation of HIV/AIDS drugs: novel and developmental antiHIV drugs and targets.

There are presently 42 million people worldwide living with HIV/AIDS, the majority of which have limited access to antiretrovirals. Even if worldwide penetration was possible, our current chemotherapeutic strategies still suffer from issues of cost, patient compliance, deleterious acute and chronic side effects, emerging single and multidrug resistance, and generalized treatment and economic issues. Even our best antiretroviral therapeutic strategy, highly active antiretroviral therapy (HAART), falls short of completely suppressing HIV replication.

Functional redundancy of the human CCL4 and CCL4L1 chemokine genes.

CCL4 and CCL4L1 are two CC chemokine genes located at chromosome 17q21 whose mature proteins differ at only a single amino acid. Abundant functional information exists for CCL4, however, CCL4L1 has only recently been recognized as a distinct gene, thus information describing it is wanting. The CCL4L1 protein was synthesized in Escherichia coli and compared with the CCL4 protein.

Anti-AIDS agents. 52. Synthesis and anti-HIV activity of hydroxymethyl (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives.

To enhance the water solubility and oral bioavailability of DCK analogues, 12 new mono- and disubstituted (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 3-Hydroxymethyl-4-methyl-DCK (4c) exhibited significant anti-HIV activity in H9 lymphocytes and primary peripheral blood mononuclear cells with EC(50) values of 0.004 and 0.

Antiviral activity of hop constituents against a series of DNA and RNA viruses.

We investigated whether crude hop extracts and purified hop components representing every major chemical class of hop compound have antiviral activity. These hop constituents were tested for antiviral activity against bovine viral diarrhea virus (BVDV) as a surrogate model of hepatitis C virus (HCV), human immunodeficiency virus (HIV), influenza A virus (FLU-A), influenza B virus (FLU-B), rhinovirus (Rhino), respiratory syncytial virus (RSV), yellow fever virus (YFV), cytomegalovirus (CMV), hepatitis B virus (HBV), and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The extracts all failed to prevent the replication of HIV, FLU-A, FLU-B, RSV and YFV.

Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1.

Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication.

Potent anti-influenza activity of cyanovirin-N and interactions with viral hemagglutinin.

The novel antiviral protein cyanovirin-N (CV-N) was initially discovered based on its potent activity against the human immunodeficiency virus (HIV). Subsequent studies identified the HIV envelope glycoproteins gp120 and gp41 as molecular targets of CV-N. More recently, mechanistic studies have shown that certain high-mannose oligosaccharides (oligomannose-8 and oligomannose-9) found on the HIV envelope glycoproteins comprise the specific sites to which CV-N binds.

In vivo antiviral activity of novel human immunodeficiency virus type 1 nucleocapsid p7 zinc finger inhibitors in a transgenic murine model.

Control of human immunodeficiency virus through the use of inexpensive chemotherapeutics, with minimal side effects and decreased potential for engendering resistant virus, is a long-term therapeutic goal. In principle, this goal can be accomplished if viral replication in reservoirs of chronically and latently infected cells is addressed. As a first step, we have developed novel antiviral compounds based on a 2-mercaptobenzamide thioester chemotype, including the pyridinioalkanoyl thioesters, which specifically target the zinc fingers of the human immunodeficiency virus nucleocapsid protein (NCp7).

A potent novel anti-HIV protein from the cultured cyanobacterium Scytonema varium.

A new anti-HIV protein, scytovirin, was isolated from aqueous extracts of the cultured cyanobacterium Scytonema varium. The protein displayed potent anticytopathic activity against laboratory strains and primary isolates of HIV-1 with EC50 values ranging from 0.3 to 22 nM.