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Introduction: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-na[euro]ive PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Methods: Adult, treatment-na[euro]ive PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and [CD4.sup.+] cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years. Results: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI- and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline [CD4.sup.+] cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI). Conclusions: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration. Keywords: integrase inhibitors; weight gain; obesity; metabolic; HIV; North America, 1 | INTRODUCTION Weight gain following antiretroviral therapy (ART) initiation is common among persons with HIV (PWH), particularly those with more pronounced [CD4.sup.+] cell count (CD4) depletion or lower pre-ART [...]

We propose a systematic approach for a better understanding of how HIV viruses employ various combinations of mutations to resist drug treatments, which is critical to developing new drugs and optimizing the use of existing drugs. By probabilistically modeling mutations in the HIV-1 protease or reverse transcriptase (RT) isolated from drug-treated patients, we present a statistical procedure that first detects mutation combinations associated with drug resistance and then infers detailed interaction structures of these mutations. The molecular basis of our statistical predictions is further studied by using molecular dynamics simulations and free energy calculations. We have demonstrated the usefulness of this systematic procedure on three HIV drugs, (Indinavir, Zidovudine, and Nevirapine), discovered unique interaction features between viral mutations induced by these drugs, and revealed the structural basis of such interactions. Bayesian model selection | free energy calculation | Markov chain Monte Carlo | molecular dynamics I mutation interactions doi/ 10.1073/pnas.0907304107

Various lectins have attracted attention as potential microbicides to prevent HIV transmission. Their capacity to bind glycoproteins has been suggested as a means to block HIV binding and entry into susceptible cells. The previously undescribed lectin actinohivin (AH), isolated by us from an actinomycete, exhibits potent in vitro anti-HIV activity by binding to high-mannose (Man) type glycans (HMTGs) of gp120, an envelope glycoprotein of HIV. AH contains 114 aa and consists of three segments, all of which need to show high affinity to gp120 for the anti-HIV characteristic. To generate the needed mechanistic understanding of AH binding to HIV in anticipation of seeking approval for human testing as a microbicide, we have used multiple molecular tools to characterize it. AH showed a weak affinity to Man[alpha](1-2)Man, Man[alpha](1-2)Man[alpha](1-2)Man, of HMTG (Man8 or Man9) or RNase B (which has a single HMTG), but exhibited a strong and highly specific affinity ([K.sub.d] = 3.4 x [10.sup.-8] M) to gp120 of HIV, which contains multiple Man8 and/or Man9 units. We have compared AH to an alternative lectin, cyanovirin-N, which did not display similar levels of discrimination between high- and low-density HMTGs. X-ray crystal analysis of AH revealed a 3D structure containing three sugar-binding pockets. Thus, the strong specific affinity of AH to gp120 is considered to be due to multivalent interaction of the three sugar-binding pockets with three HMTGs of gp120 via the 'cluster effect' of lectin. Thus, AH is a good candidate for investigation as a safe microbicide to help prevent HIV transmission. action mechanism | anti-HIV | gp120 | high-mannose type glycan | cyanovirin-N

The current testing of anti-HIV drugs is hampered by the lack of a small animal that is readily available and easy to handle; can be infected systemically with HIV type 1 (HIV-1); harbors the major HIV-1 target cells in a physiological frequency, organ distribution, and activation state; and is established as a pharmacological model. Here, we explored the potential of outbred Sprague-Dawley rats that transgenically express the HIV-1 receptor complex on CD4 T cells and macrophages as a model for the preclinical evaluation of inhibitors targeting virus entry or reverse transcription. The concentrations of the peptidic fusion inhibitor enfuvirtide or the nonnucleoside reverse transcriptase inhibitor efavirenz required to inhibit HIV-1 infection of cultured primary CD4 T cells and macrophages from human CD4 and CCR5-transgenic rats differed by no more than 3-fold from those required for human reference cultures. Prophylactic treatment of double-transgenic rats with a weight-adapted pediatric dosing regimen for either enfuvirtide (s.c., twice-daily) or efavirenz (oral, once-daily) achieved a 92.5% or 98.8% reduction, respectively, of the HIV-1 cDNA load in the spleen 4 days after i.v. HIV-1 challenge. Notably, a once-daily dosing regimen for enfuvirtide resulted in a [approximately equal to] 5-fold weaker inhibition of infection, unmasking the unfavorable pharmacokinetic characteristics of the synthetic peptide in the context of an efficacy trial. This work provides proof of principle that HIV-susceptible transgenic rats can allow a rapid and predictive preclinical evaluation of the inhibitory potency and of the pharmacokinetic properties of antiviral compounds targeting early steps in the HIV replication cycle. animal model | drugs | efficacy trial

The successful development of a number of HIV-1 protease (PR) inhibitors for the treatment of AIDS has validated the utilization of retroviral PRs as drug targets and necessitated their detailed structural study. Here we report the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substrate-based inhibitor bound in subsites P5 through PS'. Although HTLV-1 PR exhibits an overall fold similar to other retroviral PRs, significant structural differences are present in several loop areas, which include the functionally important flaps, previously considered to be structurally highly conserved. Potential key residues responsible for the resistance of HTLV-1 PR to anti-HIV drugs are identified. We expect that the knowledge accumulated during the development of anti-HIV drugs, particularly in overcoming drug resistance, will help in designing a novel class of antileukemia drugs targeting HTLV-1 PR and in predicting their drug-resistance profile. The structure presented here can be used as a starting point for the development of such anticancer therapies. inhibitor | leukemia | retroviral protease

The likelihood, and predictors, of the emergence of incident mutations associated with reduced antiretroviral drug susceptibility, among patients maintained on a potent combination therapy with persistent detectable plasma HIV-1 RNA is estimated. The likelihood of acquiring drug resistance mutations while remaining on potent combination antiretroviral therapy that does not confer complete suppression of HIV replication is relatively low and depends on the level of viral replication and prior resistance.

The macrocyclic antiviral drug xylyl-bicyclam blocks entry of HIV into cells by targeting the CXCR4 coreceptor, a seven-helix transmembrane G-protein-coupled receptor. Its affinity for CXCR4 is enhanced by binding to [Cu.sup.2+], [Ni.sup.2+], or [Zn.sup.2+]. Metallocyclams have a rich configurational chemistry and proteins may bind selectively to specific metallocyclam configurations. Our studies of lysozyme reveal structural details of protein-metallocyclam interactions that are important for receptor recognition. Solution NMR studies show that Cu-cyclam interacts with specific tryptophan residues of lysozyme (Trp-62, Trp-63, and Trp-123). Two major binding sites for both Cu-cyclam and [Cu.sub.2]-xylyl-bicyclam were detected by x-ray crystallography. In the first site, [Cu.sup.2+] in one cyclam ring of [Cu.sub.2]-xylyl-bicyclam adopts a trans configuration and is coordinated to a carboxylate oxygen of Asp-101, whereas for Cu-cyclam two ring NH groups form H bonds to the carboxylate oxygens of Asp-101, stabilizing an unusual cis (folded) cyclam configuration. For both complexes in this site, a cyclam ring is sandwiched between the indole side chains of two tryptophan residues (Trp-62 and Trp-63). In the second site, a trans cyclam ring is stacked on Trp-123 and H bonded to the backbone carbonyl of Gly-117. We show that there is a pocket in a model of the human CXCR4 coreceptor in which trans and cis configurations of metallobicyclam can bind by direct metal coordination to carboxylate side chains, cyclam-NH ... carboxylate H bonding, together with hydrophobic interactions with tryptophan residues. These studies provide a structural basis for the design of macrocycles that bind stereospecifically to G-coupled and other protein receptors. zinc | copper | x-ray crystallography | NMR | CXCR4 coreceptor

Drug therapy against wild-type HIV may lead to the development of drug resistance and treatment failure. On the other hand, drug therapy against minor strains is less likely to cause resistance.

Protease inhibitors may inhibit viral reproduction even if they don't reduce viral levels substantially. This may explain why some HIV patients who take protease inhibitors experience an increase in CD4+ T cell counts even though viral levels don't decrease.

Two drugs that block different steps during the attachment of HIV to cell membranes appear to work better together than they do separately. One drug blocks the CXCR4 cell receptor for HIV and the other is a synthetic version of the viral protein gp41 that blocks fusion to cell membranes.

The flexibility of the lactone methodology for the synthesis of axially chiral target biaryl molecules capable of accommodating any substitution pattern is presented. Research describes a synthetic strategy for the preparation of antimalarial korupensamines A and B and their anti-HIV dimers via a lactone precursor.

Roger MacKenzie [1] David Newman [2] Max M. Burger [3] Rene Roy [4] William J. Kuhns [5] Studies of the Microciona aggregation factor (MAF) have thus far been focused upon [...]

HIV drug therapy often fails because of the appearance of multidrug-resistant virus. There are two possible scenarios for the outgrowth of multidrug-resistant virus in response to therapy. Resistant virus may preexist at low frequencies in drug-naive patients and is rapidly selected in the presence of drugs. Alternatively, resistant virus is absent at the start of therapy but is generated by residual viral replication during therapy. Currently available experimental methods are generally too insensitive to distinguish between these two scenarios. Here we use deterministic and stochastic models to investigate the origin of multidrug resistance. We quantify the probabilities that resistant mutants preexist, and that resistant mutants are generated during therapy. The models suggest that under a wide range of conditions, treatment failure is most likely caused by the preexistence of resistant mutants.

HIV-1 entry into [CD.sup.4+] cells requires the sequential interactions of the viral envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors CCR5 and CXCR4. A plausible approach to blocking this process is to use small molecule antagonists of coreceptor function. One such inhibitor has been described for CCR5: the TAK-779 molecule. To facilitate the further development of entry inhibitors as antiviral drugs, we have explored how TAK-779 acts to prevent HIV-1 infection, and we have mapped its site of interaction with CCR5. We find that TAK-779 inhibits HIV-1 replication at the membrane fusion stage by blocking the interaction of the viral surface glycoprotein gp120 with CCR5. We could identify no amino acid substitutions within the extracellular domain of CCR5 that affected the antiviral action of TAK-779. However, alanine scanning mutagenesis of the transmembrane domains revealed that the binding site for TAK-779 on CCR5 is located near the extracellular surface of the receptor, within a cavity formed between transmembrane helices 1, 2, 3, and 7.

HIV-1 entry into cells is an attractive target for new antiviral agents, but some wonder whether inhibitors aimed at the CCR5 coreceptor force HIV-1 to evolve more virulent versions of itself. With CD4, CCR5 and CXCR4, coreceptors on the cell surface, mediate virus binding and membrane fusion. CCR5 is apparently dispensable for normal health, but CXCR4 is not.