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Susan Allen

Publications and source records attributed to Susan Allen.

27 records · Page 2Linked to original sources
PubMed2004

Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission.

Heterosexual transmission accounts for the majority of human immunodeficiency virus-1 (HIV-1) infections worldwide, yet the viral properties that determine transmission fitness or outgrowth have not been elucidated. Here we show, for eight heterosexual transmission pairs, that recipient viruses were monophyletic, encoding compact, glycan-restricted envelope glycoproteins. These viruses were also uniquely sensitive to neutralization by antibody from the transmitting partner. Thus, the exposure of neutralizing epitopes, which are lost in chronic infection because of immune escape, appears to be favored in the newly infected host. This reveals characteristics of the envelope glycoprotein that influence HIV-1 transmission and may have implications for vaccine design.

AIDS Vaccines↗
PubMed2004

HLA allele sharing and HIV type 1 viremia in seroconverting Zambians with known transmitting partners.

Rapid HIV type 1 (HIV-1) mutation coupled with immune evasion poses a major obstacle to effective interventions. In particular, transmission of HIV-1 from a donor partner (transmitter) to a recipient (seroconverter) with similar antigen-presenting molecules (i.e., human leukocyte antigens, HLA) may favor or expedite viral adaptation to host immune responses. Our PCR-based HLA-A, HLA-B, and HLA-DRB1 genotyping for 115 Zambian couples with documented intracouple HIV-1 (mostly clade C) transmission revealed that single-locus HLA allele sharing ranged from 28 to 36%. Different degrees of allele sharing, at single or multiple HLA loci between donor-recipient pairs, were associated with only modest increases in seroconverter RNA level (+0.04 to + 0.24 log(10) copies/mL, p > 0.25). Thus, partial HLA allele sharing commonly seen in Zambian couples did not appear to confer unequivocal early advantage for viral replication in the newly seroconverting subjects. However, correlation of virus loads in seroconverters with those of their known index partners (adjusted Pearson r = 0.21, p = 0.03) did imply that viral characteristics can independently contribute to variability in plasma virus load.

Adult↗
PubMed2004

Hierarchical targeting of subtype C human immunodeficiency virus type 1 proteins by CD8+ T cells: correlation with viral load.

An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

Amino Acid Sequence↗
PubMed2003

Sexual behavior of HIV discordant couples after HIV counseling and testing.

BACKGROUND AND OBJECTIVES: Sexual behavior following voluntary HIV counseling and testing (VCT) is described in 963 cohabiting heterosexual couples with one HIV positive and one HIV negative partner ('discordant couples'). Biological markers were used to assess the validity of self-report. METHODS: Couples were recruited from a same-day VCT center in Lusaka, Zambia. Sexual exposures with and without condoms were recorded at 3-monthly intervals. Sperm detected on vaginal smears, pregnancy, and sexually transmitted diseases (STD) including HIV, gonorrhea, syphilis, and Trichomonas vaginalis were assessed. RESULTS: Less than 3% of couples reported current condom use prior to VCT. In the year after VCT, > 80% of reported acts of intercourse in discordant couples included condom use. Reporting 100% condom use was associated with 39-70% reductions in biological markers; however most intervals with reported unprotected sex were negative for all biological markers. Under-reporting was common: 50% of sperm and 32% of pregnancies and HIV transmissions were detected when couples had reported always using condoms. Positive laboratory tests for STD and reported extramarital sex were relatively infrequent. DNA sequencing confirmed that 87% of new HIV infections were acquired from the spouse. CONCLUSIONS: Joint VCT prompted sustained but imperfect condom use in HIV discordant couples. Biological markers were insensitive but provided evidence for a significant under-reporting of unprotected sex. Strategies that encourage truthful reporting of sexual behavior and sensitive biological markers of exposure are urgently needed. The impact of prevention programs should be assessed with both behavioral and biological measures.

Adult↗
PubMed2003

Codon usage optimization of HIV type 1 subtype C gag, pol, env, and nef genes: in vitro expression and immune responses in DNA-vaccinated mice.

Codon usage optimization of human immunodeficiency virus type 1 (HIV-1) structural genes has been shown to increase protein expression in vitro as well as in the context of DNA vaccines in vivo; however, all optimized genes reported thus far are derived from HIV-1 (group M) subtype B viruses. Here, we report the generation and biological characterization of codon usage-optimized gag, pol, env (gp160, gp140, gp120), and nef genes from a primary (nonrecombinant) HIV-1 subtype C isolate. After transfection into 293T cells, optimized subtype C genes expressed one to two orders of magnitude more protein (as determined by immunoblot densitometry) than the corresponding wild-type constructs. This effect was most pronounced for gp160, gp140, Gag, and Pol (>250-fold), but was also observed for gp120 and Nef (45- and 20-fold, respectively). Optimized gp160- and gp140-derived glycoproteins were processed, incorporated into virus particles, and mediated virus entry when expressed in trans to complement an env-minus HIV-1 provirus. Mice immunized with optimized gp140 DNA developed antibody as well as CD4+ and CD8+ T cell immune responses that were orders of magnitude greater than those of mice immunized with wild-type gp140 DNA. These data confirm and extend previous studies of codon usage optimization of HIV-1 genes to the most prevalent group M subtype. Our panel of matched optimized and wild-type subtype C genes should prove valuable for studies of protein expression and function, the generation of subtype-specific immunological reagents, and the production of DNA-based sub-unit vaccines directed against a broader spectrum of viruses.

AIDS Vaccines↗
PubMed2002

Rare and new V3 loop variants in HIV-1-positive long-term non-progressors from Rwanda.

We identified uncommon amino acid substitutions in the V3 loop regions of HIV-1 strains infecting patients from Rwanda. Their frequency was greater in long-term non-progressors (LTNP) compared with late-stage patients (P = 0.006), particularly in a sequence region that has crucial interactions with the cell surface, and is highly relevant for the host's immune response. These variants might reflect a viral response to a strong immune pressure, or represent attenuated HIV-1 strains infecting LTNP in Rwanda.

Amino Acid Sequence↗
PubMed2002

Molecular epidemiology of human immunodeficiency virus type 1 transmission in a heterosexual cohort of discordant couples in Zambia.

Most human immunodeficiency virus type 1 (HIV-1) transmissions in sub-Saharan Africa are believed to occur between married adults who are discordant for their HIV-1 infection status; however, no studies to date have investigated the molecular epidemiology of such transmission events. Here we report the genetic characterization of HIV-1 strains from 149 transmission pairs that were identified prospectively in a cohort of discordant couples in Lusaka, Zambia. Subgenomic gag, gp120, gp41, and/or long terminal repeat regions were amplified by PCR analysis of uncultured blood samples from both partners and sequenced without interim cloning. Pairwise genetic distances were calculated for the regions analyzed and compared to those of subtype-specific reference sequences as well as local controls. Sequence relationships were also examined by phylogenetic tree analysis. By these approaches, epidemiological linkage was established for the majority of transmission pairs. Viruses from 129 of the 149 couples (87%) were very closely related and clustered together in phylogenetic trees in a statistically highly significant manner. In contrast, viruses from 20 of the 149 couples (13%) were only distantly related in two independent genomic regions, thus ruling out transmission between the two partners. The great majority (95%) of transmitted viruses were of subtype C origin, although representatives of subtypes A, D, G, and J were also identified. There was no evidence for extensive transmission networks within the cohort, although two phylogenetic subclusters of viruses infecting two couples each were identified. Taken together, these data indicate that molecular epidemiological analyses of presumed transmission pairs are both feasible and required to determine behavioral, virological, and immunological correlates of heterosexual transmission in sub-Saharan Africa with a high level of accuracy.

Cohort Studies↗
PubMed2002

Favorable and unfavorable HLA class I alleles and haplotypes in Zambians predominantly infected with clade C human immunodeficiency virus type 1.

The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8(+) cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log(10) VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log(10) VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.

Adult↗