HIV Replication Under High-Level Cabotegravir Is Associated with the Appearance of 3'-PPT Mutations, Circular DNA Transcription and Recombination.

The HIV integrase inhibitor, dolutegravir (DTG), in the absence of eliciting integrase (int) resistance, has been reported to select mutations in the virus 3'-polypurine tract (3'-PPT) adjacent to the 3'-LTR U3. An analog of DTG, cabotegravir (CAB), has a high genetic barrier to drug resistance and is used in formulations for treatment and long-acting pre-exposure prophylaxis. We examined whether mutations observed for DTG would emerge in vitro with CAB.

Single oral dose for HIV pre or post-exposure prophylaxis: user desirability and biological efficacy in macaques.

Background: Daily oral pre- or post-exposure prophylaxis (PrEP or PEP) is highly effective in preventing HIV infection. However, many people find it challenging to adhere to a daily oral regimen. Chemoprophylaxis with single oral doses of antiretroviral drugs taken before or after sex may better adapt to changing or unanticipated sexual practices and be a desirable alternative to daily PrEP or PEP.

Efficacy of Oral Tenofovir Alafenamide/Emtricitabine Combination or Single-Agent Tenofovir Alafenamide Against Vaginal Simian Human Immunodeficiency Virus Infection in Macaques.

Background: Tenofovir alafenamide (TAF)-based regimens are being evaluated for pre-exposure prophylaxis (PrEP). We used a macaque model of repeated exposures to simian human immunodeficiency virus (SHIV) to investigate whether TAF alone or the combination of TAF and emtricitabine (FTC) can prevent vaginal infection.

Methods: Pigtail macaques were exposed vaginally to SHIV162p3 once a week for up to 15 weeks.

Drug resistance emergence in macaques administered cabotegravir long-acting for pre-exposure prophylaxis during acute SHIV infection.

A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP.

On the Death Rate of Abortively Infected Cells: Estimation from Simian-Human Immunodeficiency Virus Infection.

Progressive T cell depletion during chronic human immunodeficiency virus type 1 (HIV) infection is a key mechanism that leads to the development of AIDS. Recent studies have suggested that most T cells in the tissue die through pyroptosis triggered by abortive infection, i.e.

Antiretroviral Drug Activity in Macaques Infected during Pre-Exposure Prophylaxis Has a Transient Effect on Cell-Associated SHIV DNA Reservoirs.

Background: Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) is a novel HIV prevention strategy. Suboptimal PrEP adherence and HIV infection creates an opportunity for continued antiretroviral drug activity during undiagnosed infection. We previously showed that macaques infected with SHIV during PrEP with FTC/TDF display reduced acute plasma viremias and limited virus diversity.

Efficacy of topical tenofovir against transmission of a tenofovir-resistant SHIV in macaques.

Background: Topically delivered tenofovir (TFV) from intravaginal rings, tablets, or gels is being evaluated for HIV prevention. We previously demonstrated that TFV delivered vaginally by gel protected macaques from vaginal infection with SHIV. Here we investigated efficacy of the TFV gel against vaginal transmission of a TFV-resistant SHIV containing the K65R mutation (SHIV162P3K65R) and its relationship to drug levels in vaginal tissues.

Prophylactic efficacy of oral emtricitabine and tenofovir disoproxil fumarate combination therapy against a tenofovir-resistant simian/human immunodeficiency virus containing the K65R mutation in macaques.

Daily preexposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is a novel strategy for preventing human immunodeficiency virus infection. We investigated in macaques whether FTC/TDF prevents transmission of a tenofovir-resistant simian/human immunodeficiency virus (SHIV) containing the K65R mutation. Six macaques received weekly a dose of FTC/TDF 3 days before rectal SHIV exposures and a second dose 2 hours after.

Reduced inflammation and CD4 loss in acute SHIV infection during oral pre-exposure prophylaxis.

Background: The impact of pre-exposure prophylaxis (PrEP) with antiretrovirals on breakthrough HIV or SHIV infection is not fully documented. We addressed the hypothesis that SHIV(SF162P3) infection despite active PrEP results in altered early immune parameters, compared with untreated infection.

Methods: Eleven rhesus macaques were infected during repeated, rectal, low-dose SHIV(SF162P3) exposures while receiving concurrent oral PrEP (Truvada [n = 2] or GS7340 [n = 4]) or as untreated controls (n = 5).

Delayed maturation of antibody avidity but not seroconversion in rhesus macaques infected with simian HIV during oral pre-exposure prophylaxis.

Background: Pre-exposure prophylaxis (PrEP) is a novel intervention strategy for the prevention HIV transmission. Because several clinical trials are at various stages of completion, it is important to understand the impact of PrEP treatment on the development of the immune response to HIV, particularly in individuals who exhibit breakthrough infections despite PrEP.

Methods: A model of HIV infection, using rhesus macaques and the simian/human immunodeficiency virus (SHIV), was used to evaluate the effects of PrEP on the evolution of the humoral immune response.

Protection against rectal transmission of an emtricitabine-resistant simian/human immunodeficiency virus SHIV162p3M184V mutant by intermittent prophylaxis with Truvada.

Daily preexposure prophylaxis (PrEP) with Truvada (emtricitabine [FTC] and tenofovir disoproxil fumarate [TDF]) is a novel HIV prevention strategy recently found to reduce HIV incidence among men who have sex with men. We used a macaque model of HIV transmission to investigate if Truvada maintains prophylactic efficacy against an FTC-resistant isolate containing the M184V mutation. Five macaques received a dose of Truvada 3 days before exposing them rectally to the simian/human immunodeficiency virus mutant SHIV162p3(M184V), followed by a second dose 2 h after exposure.

T cell chemo-vaccination effects after repeated mucosal SHIV exposures and oral pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e.

Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors.

Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures.

Generation and mucosal transmissibility of emtricitabine- and tenofovir-resistant SHIV162P3 mutants in macaques.

Transmission of drug-resistant HIV has been widely documented. We generated tenofovir (TFV)- and emtricitabine (FTC)-resistant SHIV162P3 mutants that can be used to investigate the transmission efficiency of drug-resistant viruses and their impact on the efficacy of pre-exposure prophylaxis. Both SHIV162p3(M184V) and SHIV162p3(K65R) replicated in vitro at high titers.

Intermittent prophylaxis with oral truvada protects macaques from rectal SHIV infection.

HIV continues to spread globally, mainly through sexual contact. Despite advances in treatment and care, preventing transmission with vaccines or microbicides has proven difficult. A promising strategy to avoid transmission is prophylactic treatment with antiretroviral drugs before exposure to HIV.

On-line coupling of anion exchange and ion-pair chromatography for measurement of intracellular triphosphate metabolites of reverse transcriptase inhibitors.

We developed an automated on-line weak anion exchange (WAX) solid-phase extraction (SPE) method coupled with ion-pair (IP) chromatography-tandem mass spectrometry (MS/MS) detection for quantitatively measuring triphosphorylated metabolites of three reverse transcriptase inhibitors (RTI). The administered pro-drugs were Tenofovir disoproxil fumarate (TDF), Emtricitabine (FTC) and Lamivudine (3TC). Their intracellular metabolites Tenofovir-diphosphate (TFV-DP), Emtricitabine-triphosphate (FTC-TP), and Lamivudine-triphosphate (3TC-TP) were measured in peripheral blood mononuclear cells (PBMC).

Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine.

New-generation gels that deliver potent antiretroviral drugs against human immunodeficiency virus type 1 have renewed hopes for topical prophylaxis as a prevention strategy. Previous preclinical research with monkey models suggested that high concentrations and drug combinations are needed for high efficacy. We evaluated two long-acting reverse transcriptase inhibitors, tenofovir (TFV) and emtricitabine (FTC), by using a twice-weekly repeat challenge macaque model and showed that a preexposure vaginal application of gel with 1% TFV alone or in combination with 5% FTC fully protected macaques from a total of 20 exposures to simian-human immunodeficiency virus SF162p3.

Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir.

Background: In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission.

Clinical and virological characterization of persistent human infection with simian foamy viruses.

Persons occupationally exposed to nonhuman primates (NHPs) can be persistently infected with simian foamy virus (SFV). The clinical significance and person-to-person transmissibility of zoonotic SFV infection is unclear. Seven SFV-infected men responded to annual structured interviews and provided whole blood, oral, and urogenital specimens for study.

Simple PCR assays improve the sensitivity of HIV-1 subtype B drug resistance testing and allow linking of resistance mutations.

Background: The success of antiretroviral therapy is known to be compromised by drug-resistant HIV-1 at frequencies detectable by conventional bulk sequencing. Currently, there is a need to assess the clinical consequences of low-frequency drug resistant variants occurring below the detection limit of conventional genotyping. Sensitive detection of drug-resistant subpopulations, however, requires simple and practical methods for routine testing.

The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions.

It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q.

Natural resistance of human immunodeficiency virus type 2 to zidovudine.

Zidovudine (AZT) is a reverse transcriptase (RT) inhibitor widely used to treat persons infected with HIV-1 and HIV-2. Recent data on treated patients suggest differences in the antiviral activity of AZT between HIV-1 and HIV-2. We evaluated the antiviral activity of AZT on HIV-2 by using multiple approaches including in vitro selection experiments, analysis of growth kinetics with AZT, and phenotypic testing.

Ancient co-speciation of simian foamy viruses and primates.

Although parasite-host co-speciation is a long-held hypothesis, convincing evidence for long-term co-speciation remains elusive, largely because of small numbers of hosts and parasites studied and uncertainty over rates of evolutionary change. Co-speciation is especially rare in RNA viruses, in which cross-species transfer is the dominant mode of evolution. Simian foamy viruses (SFVs) are ubiquitous, non-pathogenic retroviruses that infect all primates.

Frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates.

The recognition that AIDS originated as a zoonosis heightens public health concerns associated with human infection by simian retroviruses endemic in nonhuman primates (NHPs). These retroviruses include simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus (STLV), simian type D retrovirus (SRV), and simian foamy virus (SFV). Although occasional infection with SIV, SRV, or SFV in persons occupationally exposed to NHPs has been reported, the characteristics and significance of these zoonotic infections are not fully defined.