Smith RJ, Okano JT, Kahn JS, Bodine EN, Blower S. Evolutionary dynamics of complex networks of HIV drug-resistant strains: the case of San Francisco

Center for Biomedical Modeling, Semel Institute of Neuroscience & Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90024, USA.
Science (Impact Factor: 33.61). 02/2010; 327(5966):697-701. DOI: 10.1126/science.1180556
Source: PubMed


Over the past two decades, HIV resistance to antiretroviral drugs (ARVs) has risen to high levels in the wealthier countries of the world, which are able to afford widespread treatment. We have gained insights into the evolution and transmission dynamics of ARV resistance by designing a biologically complex multistrain network model. With this model, we traced the evolutionary history of ARV resistance in San Francisco and predict its future dynamics. By using classification and regression trees, we identified the key immunologic, virologic, and treatment factors that increase ARV resistance. Our modeling shows that 60% of the currently circulating ARV-resistant strains in San Francisco are capable of causing self-sustaining epidemics, because each individual infected with one of these strains can cause, on average, more than one new resistant infection. It is possible that a new wave of ARV-resistant strains that pose a substantial threat to global public health is emerging.

Download full-text


Available from: Sally Blower, Feb 28, 2014
  • Source
    • "The introduction of highly active antiretroviral therapy (HAART) has significantly decreased morbidity and mortality among HIV-1-infected patients with access to these drugs. However, the development of drug resistance and issues related to drug tolerability and compliance often pose a considerable challenge to current therapies [4-8]. These concerns, together with recent reports of failure in clinical trials of HIV vaccines and several microbicides, reinforce the critical need to identify new targets for the development of novel classes of anti-HIV-1 drugs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 muM) compared to CAI (Kd ~ 15 muM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates. In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical alpha-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively. The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.
    Retrovirology 11/2013; 10(1):136. DOI:10.1186/1742-4690-10-136 · 4.19 Impact Factor
  • Source
    • "Fourth, an analysis of RC does not account for the emergence and transmission of drug-resistant strains. When resistance emerges, multiple Rc's need to be evaluated in order to determine if elimination is (theoretically) possible [12], [13], [17] In addition, it needs to be understood the conditions that reduce RC to below one (e.g., the degree of viral suppression that reduces infectivity to 96%) would need to be continuously maintained until all of the treated individuals have died. Incidence would increase if the necessary conditions were not continuously maintained. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In South Africa (SA) universal access to treatment for HIV-infected individuals in need has yet to be achieved. Currently ∼1 million receive treatment, but an additional 1.6 million are in need. It is being debated whether to use a universal 'test and treat' (T&T) strategy to try to eliminate HIV in SA; treatment reduces infectivity and hence transmission. Under a T&T strategy all HIV-infected individuals would receive treatment whether in need or not. This would require treating 5 million individuals almost immediately and providing treatment for several decades. We use a validated mathematical model to predict impact and costs of: (i) a universal T&T strategy and (ii) achieving universal access to treatment. Using modeling the WHO has predicted a universal T&T strategy in SA would eliminate HIV within a decade, and (after 40 years) cost ∼$10 billion less than achieving universal access. In contrast, we predict a universal T&T strategy in SA could eliminate HIV, but take 40 years and cost ∼$12 billion more than achieving universal access. We determine the difference in predictions is because the WHO has under-estimated survival time on treatment and ignored the risk of resistance. We predict, after 20 years, ∼2 million individuals would need second-line regimens if a universal T&T strategy is implemented versus ∼1.5 million if universal access is achieved. Costs need to be realistically estimated and multiple evaluation criteria used to compare 'treatment as prevention' with other prevention strategies. Before implementing a universal T&T strategy, which may not be sustainable, we recommend striving to achieve universal access to treatment as quickly as possible. We predict achieving universal access to treatment would be a very effective 'treatment as prevention' approach and bring the HIV epidemic in SA close to elimination, preventing ∼4 million infections after 20 years and ∼11 million after 40 years.
    PLoS ONE 09/2012; 7(9):e41212. DOI:10.1371/journal.pone.0041212 · 3.23 Impact Factor
  • Source
    • "Similarly, HIV infection continues to be a worldwide epidemic. Combination antiretroviral therapies against HIV have been successful in retarding the progress of the infection, however, these treatments are expensive and still not available to vast majority of HIV Positive individuals [11]. The poor performance of these drugs in some individuals, possibly due to acquired resistance, is a reason for the ongoing research for discovery of new AIDS drugs and HIV vaccines. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Virus proteins alter protein pathways of the host toward the synthesis of viral particles by breaking and making edges via binding to host proteins. In this study, we developed a computational approach to predict viral sequence hotspots for binding to host proteins based on sequences of viral and host proteins and literature-curated virus-host protein interactome data. We use a motif discovery algorithm repeatedly on collections of sequences of viral proteins and immediate binding partners of their host targets and choose only those motifs that are conserved on viral sequences and highly statistically enriched among binding partners of virus protein targeted host proteins. Our results match experimental data on binding sites of Nef to host proteins such as MAPK1, VAV1, LCK, HCK, HLA-A, CD4, FYN, and GNB2L1 with high statistical significance but is a poor predictor of Nef binding sites on highly flexible, hoop-like regions. Predicted hotspots recapture CD8 cell epitopes of HIV Nef highlighting their importance in modulating virus-host interactions. Host proteins potentially targeted or outcompeted by Nef appear crowding the T cell receptor, natural killer cell mediated cytotoxicity, and neurotrophin signaling pathways. Scanning of HIV Nef motifs on multiple alignments of hepatitis C protein NS5A produces results consistent with literature, indicating the potential value of the hotspot discovery in advancing our understanding of virus-host crosstalk.
    PLoS ONE 06/2011; 6(6):e20735. DOI:10.1371/journal.pone.0020735 · 3.23 Impact Factor
Show more