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Biomedical subjects

Susan J Little

Publications and source records attributed to Susan J Little.

At least 19 recordsLinked to original sources
PubMed2007

Unprotected anal intercourse and substance use before and after HIV diagnosis among recently HIV-infected men who have sex with men.

OBJECTIVE: The objective of this study was to assess associations between unprotected anal intercourse (UAI) and substance use before and after HIV diagnosis among recently HIV-infected MSM. STUDY DESIGN: Two hundred seven MSM completed computer-assisted self-interviews regarding type and timing of sexual activity and substance use with their last 3 partners. Date of HIV diagnosis was extracted from medical records. Generalized estimating equations, including interaction terms, were used to assess associations between substance use and UAI before and after HIV diagnosis. RESULTS: Among partners with whom sexual activity occurred before diagnosis, UAI was associated with methamphetamine use alone (odds ratio = 7.12) and a combination of methamphetamine and other substances (odds ratio = 4.06). However, after HIV diagnosis, UAI was associated with use of substances other than methamphetamine (odds ratio = 3.36), but not methamphetamine alone. CONCLUSIONS: Use of illicit substances may be differentially associated with UAI based on knowledge of HIV status and could have implications for prevention of HIV transmission.

Adolescent↗
PubMed2006

Characteristics of recently HIV-infected men who use the Internet to find male sex partners and sexual practices with those partners.

OBJECTIVE: To examine (1) characteristics of recently HIV-infected men who have sex with men (MSM) who find sex partners through the Internet and (2) differences in characteristics of and sexual behaviors practiced with Internet partners as compared to other partner types. METHODS: From May 2002 to 2005, a computer-assisted self-interview was administered to 194 recently HIV-infected MSM in southern California. MSM who used the Internet to find sex partners were compared with those who did not report Internet use, and partners found from the Internet were compared with those who were found from other venues using chi analyses, t tests, logistic regression, and generalized estimating equations. RESULTS: Seventy percent of participants reported using the Internet to find partners in the prior 3 months. In multivariate analysis, Internet users as compared to non-Internet users reported higher education levels (some college vs. high school: odds ratio [OR] = 5.04; P < 0.01 and college or greater vs. high school: OR = 9.61; P = 0.01), were more likely to be white (OR = 2.16; P = 0.04), reported more partners in the prior 3 months (OR = 1.05; P = 0.04), were more likely to have had sexual contact with all their last 3 partners after HIV diagnosis (OR = 3.43; P < 0.01), and were more likely to report that all their last 3 partners were HIV-negative (OR = 3.35; P = 0.02), but none were main partners (OR = 2.36; P = 0.02). When compared with partners who were found in other venues, Internet partners were less likely to be main partners (OR = 0.52; P < 0.01) and were more likely to be younger (OR = 0.98; P = 0.05), to be HIV-negative (OR = 1.88; P = 0.02), and to become sex partners after HIV diagnosis (OR = 1.58; P = 0.03). CONCLUSIONS: The Internet is a popular venue for recently HIV-infected MSM to find partners, many of whom are HIV-negative. Because finding sex partners through the Internet occurs after HIV diagnosis, the Internet could be a valuable target for new HIV prevention strategies.

Adult↗
PubMed2006

Unprotected anal intercourse and substance use among men who have sex with men with recent HIV infection.

OBJECTIVES: To examine within-subjects and combined between- and within-subjects associations between substance use and unprotected anal intercourse (UAI) among men who have sex with men (MSM) with recent HIV infection. METHODS: One hundred ninety-four MSM who were recently infected with HIV completed a computer-assisted questionnaire regarding sexual behaviors and substance use with their last 3 partners. Associations between UAI and substance use were assessed using conditional logistic regression (CLR) to assess associations among the 116 MSM reporting UAI with some but not all partners and generalized linear mixed effects models (GLMMs) to examine a combination of within- and between-subjects associations in the entire sample (N = 194). RESULTS: In multivariate CLR models and GLMMs, UAI was associated with the use of methamphetamine (odds ratio [OR] = 4.9 and OR = 3.5, respectively), marijuana (OR = 4.0 and OR = 2.2, respectively) and erectile dysfunction medications (EDMs) when used with a main partner (OR = 13.8 and OR = 10.1, respectively). CONCLUSIONS: Results indicate that a direct association may exist between specific substances and UAI and provide evidence that the use of methamphetamine and EDMs may contribute to HIV transmission.

Adult↗
PubMed2006

Greater CD4 T-cell gains after one year of antiretroviral therapy are associated with lower HIV-1 pol replication capacity.

We sought to determine whether pretreatment low pol replication capacity (polRC) is associated with CD4 T-cell count gains during antiretroviral therapy (ART). Patients were recruited at north American and Australian sites. Viral polRC was measured before starting ART in all subjects. We examined 243 individuals for a median 260 days after initiating ART. Low baseline polRC was associated with greater CD4 T-cell gains independent of virological responses.

Anti-HIV Agents↗
PubMed2006

Lack of neutralizing antibody response to HIV-1 predisposes to superinfection.

Occurrences of HIV-1 superinfection offer a unique opportunity to investigate the correlates of immune protection. Here we describe the neutralizing antibody responses of a cohort of recently infected individuals who were screened for HIV superinfection. Three individuals identified with HIV superinfection had less cross-protective and autologous neutralizing antibody response than their non-superinfected case-controls. Neutralizing antibody may be crucial in the protection against superinfection and may explain why superinfection has only been documented following recent infection or treatment interruption. These data have considerable implications for vaccine development.

Adult↗
PubMed2006

Transmission behaviors of recently HIV-infected men who have sex with men.

OBJECTIVES: Analyze postdiagnosis behaviors of recently HIV-infected men who have sex with men (MSM). METHODS: Recently HIV-infected MSM were interviewed at 6 weeks (n = 153) and 3 months (n = 113) after diagnosis. Behaviors from baseline to follow-up were compared; multivariate logistic regression identified associations between baseline characteristics and behavior at follow-up. RESULTS: At follow-up, MSM reported a significantly lower mean of partners (7.9 vs. 5.2) and lower means of 1-time (1.9 vs. 0.8), unknown (3.7 vs. 2.6), and acquaintance (1.1 vs. 0.5) partners than at baseline. In multivariate analyses, unprotected anal intercourse (UAI) with the last partner at follow-up was more likely if the last partner at baseline was a main partner (odds ratio [OR] = 2.94, 95% confidence interval [CI]: 1.04 to 8.33) or HIV-positive partner (OR = 3.36, 95% CI: 1.27 to 8.88) but less likely if, at follow-up, the last partner was HIV-negative (OR = 0.28, 95% CI: 0.08 to 1.00) or of unknown HIV status (OR = 0.23, 95% CI: 0.08 to 0.71), the participant had a history of nonconsensual sex (OR = 0.25, 95% CI: 0.09 to 0.72), or the participant had more than 1 partner (OR = 0.28, 95% CI: 0.09 to 0.86). More than 1 partner at follow-up was associated with no main partner at baseline or follow-up (OR = 2.76, 95% CI: 1.12 to 6.78), more partners in the last 12 months (OR = 1.02, 95% CI: 1.01 to 1.04), and UAI with the last partner (OR = 0.36, 95% CI: 0.14 to 0.90). CONCLUSIONS: After diagnosis, some but not all recently HIV-infected MSM reduced risky sexual behavior permitting potential HIV transmission.

California↗
PubMed2005

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection.

HIV type 1 (HIV-1) can rapidly escape from neutralizing antibody responses. The genetic basis of this escape in vivo is poorly understood. We compared the pattern of evolution of the HIV-1 env gene between individuals with recent HIV infection whose virus exhibited either a low or a high rate of escape from neutralizing antibody responses. We demonstrate that the rate of viral escape at a phenotypic level is highly variable among individuals, and is strongly correlated with the rate of amino acid substitutions. We show that dramatic escape from neutralizing antibodies can occur in the relative absence of changes in glycosylation or insertions and deletions ("indels") in the envelope; conversely, changes in glycosylation and indels occur even in the absence of neutralizing antibody responses. Comparison of our data with the predictions of a mathematical model support a mechanism in which escape from neutralizing antibodies occurs via many amino acid substitutions, with low cross-neutralization between closely related viral strains. Our results suggest that autologous neutralizing antibody responses may play a pivotal role in the diversification of HIV-1 envelope during the early stages of infection.

Adult↗
PubMed2005

HIV drug resistance acquired through superinfection.

OBJECTIVE: 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. METHODS AND DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Adult↗
PubMed2005

HIV superinfection.

Worldwide, 16 cases of HIV-1 superinfection in humans have been reported since 2002. Superinfection is defined as the reinfection of an individual who already has an established infection with a heterologous HIV strain. Controversy exists surrounding superinfection, because it has implications concerning our understanding of worldwide HIV diversity, individual immunity and disease progression, and vaccine development. Here, we review the current understanding of HIV superinfection.

AIDS-Related Opportunistic Infections↗
PubMed2005

Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1.

Patients in whom virologic suppression is achieved with highly active antiretroviral therapy (HAART) retain long-lived cellular reservoirs of human immunodeficiency virus type 1 (HIV-1); this retention is an obstacle to sustained control of infection. To assess the impact that initiating treatment during primary HIV-1 infection has on this cell population, we analyzed the decay kinetics of HIV-1 DNA and of infectivity associated with cells activated ex vivo in 27 patients who initiated therapy before or <6 months after seroconversion and in whom viremia was suppressed to <50 copies/mL. The clearance rates of cellular reservoirs could not be distinguished by these techniques (median half-life, 20 weeks) during the first year of HAART. The clearance of HIV-1 DNA slowed significantly during the subsequent 3 years of treatment (median half-life, 70 weeks), consistent with heterogeneous cellular reservoirs being present. Total cell-associated infectivity (CAI) after 1 year of treatment was undetectable (<0.07 infectious units/million cells [IUPM]) in most patients initiating treatment during primary infection either before (9/9) or <6 months after (6/8) seroconversion. In contrast, all 17 control patients who initiated HAART during chronic infection retained detectable CAI after 3-6 years of treatment (median reservoir size, 1.1 IUPM; P<.0005). These results suggest that treatment <6 months after seroconversion may facilitate long-term control of cellular reservoirs that maintain HIV-1 infection during treatment.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Characterization of human immunodeficiency virus type 1 (HIV-1) envelope variation and neutralizing antibody responses during transmission of HIV-1 subtype B.

We analyzed neutralization sensitivity and genetic variation of transmitted subtype B human immunodeficiency virus type 1 (HIV-1) in eight recently infected men who have sex with men and the virus from the six subjects who infected them. In contrast to reports of heterosexual transmission of subtype C HIV-1, in which the transmitted virus appears to be more neutralization sensitive, we demonstrate that in our study population, relatively few phenotypic changes in neutralization sensitivity or genotypic changes in envelope occurred during transmission of subtype B HIV-1. We suggest that limited genetic variation within the infecting host reduces the likelihood of selective transmission of neutralization-sensitive HIV.

Acute Disease↗
PubMed2005

Human immunodeficiency virus type 1 clade B superinfection: evidence for differential immune containment of distinct clade B strains.

Sequential infection with different strains of human immunodeficiency virus type 1 (HIV-1) is a rarely identified phenomenon with important implications for immunopathogenesis and vaccine development. Here, we identify an individual whose good initial control of viremia was lost in association with reduced containment of a superinfecting strain. Subject 2030 presented with acute symptoms of HIV-1 infection with high viremia and an incomplete seroconversion as shown by Western blotting. A low set point of viremia (approximately 1,000 HIV-1 copies/ml) was initially established without drug therapy, but a new higher set point (approximately 40,000 HIV-1 copies/ml) manifested about 5 months after infection. Drug susceptibility testing demonstrated a multidrug-resistant virus initially but a fully sensitive virus after 5 months, and an analysis of pol genotypes showed that these were two phylogenetically distinct strains of virus (strains A and B). Replication capacity assays suggested that the outgrowth of strain B was not due to higher fitness conferred by pol, and env sequences indicated that the two strains had the same R5 coreceptor phenotype. Delineation of CD8+-T-lymphocyte responses against HIV-1 showed a striking pattern of decay of the initial cellular immune responses after superinfection, followed by some adaptation of targeting to new epitopes. An examination of targeted sequences suggested that differences in the recognized epitopes contributed to the poor immune containment of strain B. In conclusion, the rapid overgrowth of a superinfecting strain of HIV-1 of the same subtype raises major concerns for effective vaccine development.

AIDS Vaccines↗
PubMed2004

The prostate as a reservoir for HIV-1.

As the prostate can harbor bacterial and fungal pathogens, it was investigated as a reservoir for HIV. Nine men chronically infected with HIV participated in a crossover trial in which weekly semen samples were collected with and without previous prostate massage (PM). Six of the nine participants had undetectable seminal plasma(SP) HIV RNA in all samples without previous PM, but had detectable SP HIV RNA (> 25 copies/ml) in one to three samples collected after PM.

Cross-Over Studies↗
PubMed2004

Genetic basis of hypersusceptibility to protease inhibitors and low replicative capacity of human immunodeficiency virus type 1 strains in primary infection.

The initial virus strains from as many as 12% of individuals with primary human immunodeficiency virus (HIV) infection have a 50% inhibitory concentration </=0.4-fold that of HIV type 1(NL4-3) (HIV-1(NL4-3)) to ritonavir (hypersusceptibility [HS]). There is also substantial variation in replicative capacity (RC) or an in vitro assay of the contributions of protease (PR) and reverse transcriptase to viral fitness. In chronically infected antiretrovirally treated patients, amprenavir HS has been associated with the mutation N88S in PR, but this mutation is not seen in untreated patients. In this study, virus strains from 182 cases of primary HIV infection were analyzed, and a highly significant association between HS and low RC (</=10% that of HIV-1(NL4-3)) was observed (P < 10(-6)). Multivariate analysis was used to determine the genotypic basis of ritonavir HS, analyzing all polymorphic amino acid sites and insertions from p7gag through PR. Decision tree models developed on the entire Gag-plus-PR data set and on PR alone gave overall correct classifications of 73 and 72%, respectively, on cross-validation. They were also able to predict low RC, with sensitivities of 69 and 62% and specificities of 84 and 70%, respectively. The analysis shows that ritonavir HS in untreated primary HIV infection is not associated with single mutations but with combinations of amino acids at polymorphic sites and that the same genotypes which confer HS to PR inhibitors confer low RC. This supports the view that variation in PR function is directly responsible for variation in fitness among strains in primary infection.

Decision Trees↗
PubMed2004

HIV evolution and escape.

Human immunodeficiency virus (HIV) exemplifies the principles of Darwinian evolution with a telescoped chronology. Because of its high mutation rate and remarkably high rates of replication, evolution can be appreciated over periods of days in contrast to the durations conceived of by Darwin. Certain selective pressures that drive the evolution of HIV include chemotherapy, anatomic compartmentalization and the immune response. Examples of these selective forces on HIV evolution are described.

AIDS Vaccines↗
PubMed2003

Clade B HIV-1 superinfection with wild-type virus after primary infection with drug-resistant clade B virus.

BACKGROUND: The immunological response to HIV-1 infection has been postulated to impede superinfection with a second virus; however, a few recent reports have documented cases of HIV-1 superinfection in humans either from different viral clades or from the same clade. OBJECTIVE: To differentiate between co-infection and superinfection in a patient harboring a distinct wild-type HIV 4 months after primary infection with drug-resistant HIV. METHODS: Detailed dye primer and clonal sequencing along with length polymorphism analysis was used to investigate the evolutionary linkage between viral populations sampled at different timepoints. RESULTS: After a set point viral load of -6000 copies HIV RNA/ml, the viral load jumped to 34 000 copies/ml at month 4 and, shortly after, to almost 200 000 copies/ml. At that time a second viral strain was first detected by dye primer sequencing of a pol fragment. These findings were confirmed by analysis of a 1300 bp gag-pol fragment and clonal sequencing and phylogenetic analysis of the V3 region. Length polymorphism analysis of the gp120 V4-V5 region showed that the second viral population was absent even as a minority population until month 4, when it was found to be the majority population, and the initial variant was present only as a minority. Both strains were subtype B. CONCLUSION: These data support intraclade HIV-1 superinfection by wild-type virus in the absence of antiretroviral therapy in a patient initially infected with drug-resistant HIV. The substantially different in-vivo viral growth characteristics observed illustrate the potential for superinfection to impact disease progression.

DNA, Viral↗