George K Hightower

University of California, San Diego, San Diego, CA, United States

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Publications (10)60.23 Total impact

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    ABSTRACT: To better understand the dynamics of HIV-specific neutralizing antibody (NAb), we examined associations between viral genetic diversity and the NAb response against a multi-subtype panel of heterologous viruses in a well-characterized, therapy-naïve primary infection cohort. Using next generation sequencing (NGS), we computed sequence-based measures of diversity within HIV-1 env, gag and pol, and compared them to NAb breadth and potency as calculated by a neutralization score. Contemporaneous env diversity and the neutralization score were positively correlated (p=0.0033), as were the neutralization score and estimated duration of infection (EDI) (p=0.0038), and env diversity and EDI (p=0.0005). Neither early env diversity nor baseline viral load correlated with future NAb breadth and potency (p>0.05). Taken together, it is unlikely that neutralizing capability in our cohort was conditioned on viral diversity, but rather that env evolution was driven by the level of NAb selective pressure.
    Virology. 11/2014;
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    ABSTRACT: Characterize intra-individual HIV-1 subtype B pol evolution in antiretroviral naive individuals. Longitudinal cohort study of individuals enrolled during primary infection. Eligible individuals were antiretroviral naïve participants enrolled in the cohort from December 1997-December 2005 and having at least two blood samples available with the first one collected within a year of their estimated date of infection. Population-based pol sequences were generated from collected blood samples and analyzed for genetic divergence over time in respect to dual infection status, HLA, CD4 count and viral load. 93 participants were observed for a median of 1.8 years (Mean = 2.2 years, SD = 1.9 years). All participants classified as mono-infected had less than 0.7% divergence between any two of their pol sequences using the Tamura-Nei model (TN93), while individuals with dual infection had up to 7.0% divergence. The global substitution rates (substitutions/nucleotide/year) for mono and dually infected individuals were significantly different (p<0.001); however, substitution rates were not associated with HLA haplotype, CD4 or viral load. Even after a maximum of almost 9 years of follow-up, all mono-infected participants had less than 1% divergence between baseline and longitudinal sequences, while participants with dual infection had 10 times greater divergence. These data support the use of HIV-1 pol sequence data to evaluate transmission events, networks and HIV-1 dual infection.
    PLoS ONE 01/2013; 8(6):e68188. · 3.53 Impact Factor
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    ABSTRACT: Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.
    Virology 11/2012; 433(2):498–505. · 3.35 Impact Factor
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    ABSTRACT: Since HIV-1 Tat has been associated with neurocognitive dysfunction, we investigated 60 HIV-1 subtype B-infected individuals who were characterized for neurocognitive functioning and had paired CSF and blood plasma samples available. To avoid issues with repeated sampling, we generated population-based HIV-1 tat sequences from each compartment and evaluated these data using a battery of phylogenetic, statistical, and machine learning tools. These analyses identified position HXB2 5905 within the cysteine-rich domain of tat as a signature of CSF-derived HIV-1, and a higher number of mixed bases in CSF, as measure of diversity, was associated with HIV-associated neurocognitive disorder. Since identified mutations were synonymous, we evaluated the predicted secondary RNA structures, which showed that this mutation altered secondary structure. As a measure of divergence, the genetic distance between the blood and CSF-derived tat was inversely correlated with current and nadir CD4+ T cell counts. These data suggest that specific HIV-1 features of tat influence neurotropism and neurocognitive impairment.
    Journal of NeuroVirology 04/2012; 18(2):81-90. · 2.85 Impact Factor
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    ABSTRACT: When antiretroviral therapy does not fully suppress HIV replication, suboptimal levels of antiretrovirals can select for antiretroviral resistant variants of HIV. These variants may exhibit reduced replication capacity and result in lower viral loads in blood. Our study evaluated whether antiretroviral resistance was associated with viral loads in the cerebrospinal fluid (CSF) and better neuropsychological (NP) performance. We enrolled 94 participants and each participant underwent a comprehensive neuromedical evaluation that used structured clinical assessments of medical history, ART and other medication use, comprehensive NP testing, and neurological and general physical signs of disease. Blood was collected by venipuncture, and all participants were offered lumbar puncture. Univariate and multivariate statistical methods were used to analyze the relationship between antiretroviral resistance, blood and CSF HIV RNA levels, substance use, and NP performance. Antiretroviral resistance, detected in blood, was associated with lower CSF viral loads (p<0.01) and better NP performance (p=0.04) in multivariate analyses, independent of past and current ARV use and blood viral loads (model: p<0.01). However, HIV RNA levels in CSF did not independently correlate with NP performance. Low viral loads in the CSF limited our ability to investigate the relationship between antiretroviral resistance detected in CSF and NP performance. Even in the absence of ART, antiretroviral resistance-associated mutations correlate with better NP performance possibly because these mutations reflect reduced neurovirulence compared with wild-type HIV.
    Virology 09/2009; 394(2):243-8. · 3.35 Impact Factor
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    ABSTRACT: Human immunodeficiency virus type 1 blood plasma viral load is correlated with the sexual transmission of HIV, although transmission from men involves virus from semen instead of blood. We quantified HIV-1 RNA in the blood and semen of men who did or did not transmit HIV to their sex partners. We compared the relationships of HIV-1 transmission risk with blood plasma viral load, seminal plasma viral load, herpes simplex virus 2 serostatus and other factors. A case-control study. Participants were men evaluated for primary HIV infection and their recent male sex partners. They were interviewed, and clinical specimens were collected. Epidemiologic and phylogenetic linkages were determined by history and molecular techniques. Couples were grouped on the basis of transmission after exposure. Fisher's exact test and Wilcoxon tests were used for comparisons between groups. Multivariable logistic regressions were fit to identify independent predictors of transmission. HIV-transmitting partners (n = 15) had a higher median seminal plasma viral load (P < 0.015) and median blood plasma viral load (P < 0.001) than nontransmitting partners (n = 32). Herpes simplex virus 2 serostatus was associated with transmission only when the HIV-infected source partner was herpes simplex virus 2 seropositive and the HIV-exposed partner was not (odds ratio 16, P < 0.03). Adjusting for other factors, HIV transmission was significantly associated with blood plasma viral load (odds ratio 13.4, P < 0.02) but not seminal plasma viral load (odds ratio 0.69, P = not significant). Blood and seminal plasma viral load were both associated with human immunodeficiency virus type 1 transmission, but blood plasma viral load was the stronger predictor in this cohort. Herpes simplex virus 2 coinfection was associated with the risk of transmission but not acquisition of human immunodeficiency virus type 1.
    AIDS (London, England) 08/2008; 22(13):1667-71. · 4.91 Impact Factor
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    ABSTRACT: Transmitted drug-resistant HIV slowly reverts in the blood to drug-sensitive virus. The environment of the male genital tract (MGT) may result in even slower rates of reversion to drug susceptibility. We measured the decay of resistance in longitudinally collected blood and semen samples from 5 individuals newly infected with HIV containing resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We also investigated the sexual transmission of HIV to and from these participants. In 3 of the 5 individuals, NNRTI resistance persisted in blood and semen throughout follow-up (mean, 296 days after the estimated day of infection [EDI]). In the other 2 individuals, NNRTI resistance persisted in blood and semen for 871 and 1179 days after the EDI; however, even after NNRTI resistance had fully reverted in blood, it remained readily detectable in semen. Two transmission groups were identified among these participants--one as the recipient partner and the other as the source partner. Transmitted drug-resistant HIV, which persists in blood for years, may revert to wild type even more slowly in the MGT. This prolonged persistence in the MGT may contribute to the high prevalence rates of transmitted drug resistance.
    The Journal of Infectious Diseases 09/2007; 196(3):356-60. · 5.85 Impact Factor
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    ABSTRACT: HIV interclade B superinfection has previously been described in individuals initially infected with drug resistant virus who then become superinfected by a drug susceptible strain. We report an individual initially infected with a drug-sensitive clade B strain of HIV who was superinfected with another clade B strain resistant to two classes of antiretroviral drugs. To differentiate superinfection from possible co-infection we applied three independent molecular techniques: dye-primer sequencing of a pol fragment, length polymorphism analysis of the V4-5 coding region of the env gene and clonal sequencing of the V3 coding region of the env gene. To assess viral fitness we performed replication capacity assays of the pol gene. These investigations supported the conclusion that this was a case of superinfection and not co-infection. Coincident with acquiring the new strain, the individual's viral load increased by about 10,000 copies/ml with a decrease of 150 x CD4 T cells/mul over the next 6 months. The greater in vivo fitness of the second virus was not supported by the replication capacity assay. Furthermore, superinfection negatively impacted this individual's treatment course. It was not known that he had acquired a drug resistant strain before entering a treatment study, and he had an incomplete response to therapy most likely because the superinfecting viral strain had a decreased susceptibility to two of the prescribed medications. HIV drug resistance acquired through superinfection significantly lowers the likelihood of successful antiretroviral therapy and undermines the clinical value of a patient's prior drug resistance testing and lack of prior antiretroviral use.
    AIDS 09/2005; 19(12):1251-6. · 6.41 Impact Factor
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    JAMA The Journal of the American Medical Association 10/2004; 292(10):1177-8. · 29.98 Impact Factor

Publication Stats

226 Citations
60.23 Total Impact Points

Institutions

  • 2005–2013
    • University of California, San Diego
      • • Department of Medicine
      • • Department of Psychiatry
      San Diego, CA, United States
  • 2012
    • Yonsei University Hospital
      Sŏul, Seoul, South Korea
  • 2009
    • University of the Pacific (California - USA)
      Stockton, California, United States