A novel 24-base pair deletion in the coding region of CCR5 in an African population.
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Adult↗
Biomedical subjects
Susan Allen
Publications and source records attributed to Susan Allen.
Novel approach for differential diagnosis of HIV infections in the face of vaccine-generated antibodies: utility for detection of diverse HIV-1 subtypes.
Because increasing numbers of HIV vaccine candidates are being tested globally, it is essential to differentiate vaccine- from virus-induced antibodies. Most of the currently tested vaccines contain multiple viral components. As a result, many vaccine recipients give positive results in FDA-licensed HIV serodetection tests. We have identified conserved sequences in Env-gp41 and Gag-p6, which are recognized soon after infection but are not included in most HIV vaccine candidates. A new HIV serodetection assay, the HIV-SELECTEST, was established that distinguishes between vaccine-induced antibodies and seroconversion due to true HIV infections. It is important to make this assay globally relevant, because many clinical trials are conducted around the world where most HIV infections are due to non-B subtype HIV-1. Therefore, the current study examined the reactivity of plasma samples from >3,000 infections with diverse HIV subtypes worldwide. The HIV-SELECTEST performed at >99% specificity and sensitivity. Both recent and established infections with clades A, B, C, D, E, F, G, J, and CRFs were detected. Antibodies elicited by other vaccinations or infections endemic to the clinical trial sites did not react in this assay. Therefore, HIV-SELECTEST could be an important differential diagnostic tool for HIV vaccine trials, blood banks, and population screening worldwide.
AIDS Serodiagnosis↗
Role of V1V2 and other human immunodeficiency virus type 1 envelope domains in resistance to autologous neutralization during clade C infection.
Biologically functional clade C envelope (Env) glycoproteins from the chronically (donor) and newly (recipient) infected partners of four heterosexual transmission pairs in Zambia were cloned and characterized previously. In each case, the donor viral quasispecies contained Envs that were resistant to autologous neutralization by contemporaneous plasma, while the recipient Envs were sensitive to neutralizing antibodies in this donor plasma sample. The donor Envs also varied in length, glycosylation, and amino acid sequence of the V1V2 hypervariable domain of gp120, while the recipient Envs were much more homogeneous. To assess the contribution of V1V2 to the neutralization phenotype of the donor Envs, V1V2 domains from neutralization-sensitive recipient Envs were replaced with donor V1V2 domains, and the autologous neutralization sensitivities of the chimeric Envs were evaluated using a virus-pseudotyping assay. Long donor V1V2 domains regulated sensitivity to autologous neutralization, although the effect was dependent on the Env background. Short donor V1V2 domains did not confer neutralization resistance. Primary sequence differences in V2 were also found to influence neutralization sensitivity in one set of recipient Envs. The results demonstrate that expansion of the V1V2 domain is one pathway to escape from autologous neutralization in subtype C Envs. However, V1V2-independent mechanisms of resistance also exist, suggesting that escape is multifaceted in chronic subtype C infection.
Autoantigens↗
Genetic and neutralization properties of subtype C human immunodeficiency virus type 1 molecular env clones from acute and early heterosexually acquired infections in Southern Africa.
A standard panel of subtype C human immunodeficiency virus type 1 (HIV-1) Env-pseudotyped viruses was created by cloning, sequencing, and characterizing functional gp160 genes from 18 acute and early heterosexually acquired infections in South Africa and Zambia. In general, the gp120 region of these clones was shorter (most evident in V1 and V4) and less glycosylated compared to newly transmitted subtype B viruses, and it was underglycosylated but no different in length compared to chronic subtype C viruses. The gp120s also exhibited low amino acid sequence variability (12%) in V3 and high variability (39%) immediately downstream of V3, a feature shared with newly transmitted subtype B viruses and chronic viruses of both subtypes. When tested as Env-pseudotyped viruses in a luciferase reporter gene assay, all clones possessed an R5 phenotype and resembled primary isolates in their sensitivity to neutralization by HIV-1-positive plasmas. Results obtained with a multisubtype plasma panel suggested partial subtype preference in the neutralizing antibody response to infection. The clones were typical of subtype C in that all were resistant to 2G12 (associated with loss of N-glycosylation at position 295) and most were resistant to 2F5, but all were sensitive to 4E10 and many were sensitive to immunoglobulin G1b12. Finally, conserved neutralization epitopes in the CD4-induced coreceptor binding domain of gp120 were poorly accessible and were difficult to induce and stabilize with soluble CD4 on Env-pseudotyped viruses. These results illustrate key genetic and antigenic properties of subtype C HIV-1 that might impact the design and testing of candidate vaccines. A subset of these gp160 clones are suitable for use as reference reagents to facilitate standardized assessments of vaccine-elicited neutralizing antibody responses.
Gene Products, env↗
Group M-based HIV-1 Gag peptides are frequently targeted by T cells in chronically infected US and Zambian patients.
BACKGROUND: The enormous sequence diversity of HIV-1 has been a major obstacle in the development of a globally useful vaccine for AIDS. The consensus and ancestral sequence-based immunogens minimize the genetic distance between contemporary isolates and vaccine strains. Hence these sequences may be promising candidates for HIV vaccines or serve as a universal reagent set for evaluating Gag-specific responses. METHODS: In this study, we measured the T-cell reactivity to consensus (subtype A, B, C and group M), ancestral (group M and subtype B) and HXB2 Gag peptides (15-mers overlapping by 11) in HIV-1-infected subjects from two reference populations. We evaluated the Gag-specific T-cell responses in 43 chronically infected US (subtype B) and 13 Zambian (subtype C) subjects using an interferon-gamma enzyme-linked immunosorbent spot assay. RESULTS: Our findings demonstrate a broad cross-reactivity of nearly 70% among all the seven Gag immunogens evaluated. Consensus M sequences elicited similar levels of responses as did the consensus B, ancestral subtype B and HXB2 peptides in subtype B-infected US patients. In subtype C-infected Zambian subjects, responses of similar breadth and magnitude were elicited by consensus C, consensus M and ancestral M peptides. CONCLUSION: Our data demonstrate that peptide pools based on consensus or ancestral M-based sequences can be used to evaluate Gag-specific responses elicited by subtype B or subtype C-based immunogens.
AIDS Vaccines↗
Real-time PCR quantitation of subtype C HIV DNA in a Zambian discordant couple cohort.
To study the viral sequence diversity that is characteristic of HIV infection, PCR amplification and sequencing of viral genes is an essential step. However, a limitation of traditional PCR methods is that one viral target may be preferentially amplified over another when multiple sequences are present. This presents a particular problem when conclusions about diversity are made from one or only a few PCRs. One way to avoid resampling is to perform a large number of PCR amplifications on a single template; however, this requires that extensive dilution series be carried out on each patient sample to identify the appropriate concentration of input DNA. Here we describe the development and implementation of a quantitative real-time PCR (qPCR) method that detects a short sequence in gag and is optimized to detect subtype C HIV sequences. The standard curve was externally validated using two chronically infected cell lines carrying a known number of HIV copies per genome, and this assay yielded reproducible and accurate measurements on patient DNA samples over a wide range of input targets. The qPCR assay results were consistent with those obtained by the traditional limiting dilution method yet entailed only a fraction of the time and reagents required for the latter. This robust and quantitative real-time assay can be used to ensure that each viral sequence obtained through PCR represents a single template for studies in which the diversity of the entire population must be accurately portrayed, and can readily be applied to other research settings and viral subtypes.
Cohort Studies↗
Promoting independence for wheelchair users: the role of home accommodations.
PURPOSE: The objective of this research is to investigate whether home accommodations influence the amount of human help provided to a nationally representative sample of adults who use wheelchairs. DESIGN AND METHODS: We analyzed data from the Adult Disability Follow-back Survey (DFS), Phase II, of the Disability Supplement to the 1994-1995 National Health Interview Surveys (NHIS-D). The analytic sample consisted of 899 adults aged 18 and older who reported using wheelchairs in the previous 2 weeks. We conducted logistic regression and ordinary least squares (OLS) regression analyses to test the influence of home accommodations on the receipt of any human help, and among respondents who received help, on the hours of help received, respectively. We analyzed paid and unpaid help separately. RESULTS: Home accommodations were related to the receipt of unpaid, but not paid, help. Relative to having no home accommodations, the presence of each additional accommodation decreased the odds of having unpaid help by 14% (OR =.86; 95% CI =.76,.97). Additionally, we observed an inverse relationship between the number of accommodations in the home and hours of unpaid help (p <.01). For wheelchair users who live alone, specific types of home accommodations were also inversely related to hours of unpaid help. IMPLICATIONS: Policies that reimburse for home accommodations may be an efficient response to the growing demand for home-care support while enabling greater autonomy and independence for people who use wheelchairs.
Activities of Daily Living↗
Evidence for potent autologous neutralizing antibody titers and compact envelopes in early infection with subtype C human immunodeficiency virus type 1.
Information about neutralizing antibody responses in subtype C-infected individuals is limited, even though this viral subtype causes the majority of AIDS cases worldwide. Here we compared the course and magnitude of the autologous neutralizing antibody (NAb) response against viral envelope (Env) glycoproteins present during acute and early infection with subtypes B and C human immunodeficiency virus type 1 (HIV-1). NAb responses were evaluated in 6 subtype B-infected and 11 subtype C-infected subjects over a mean evaluation period of 25 months using a pseudovirus reporter gene assay. All subjects in the C cohort were infected through heterosexual contact, while five of the six subjects in the B cohort were infected via male-to-male contact. The kinetics and magnitude of the NAb responses varied among subjects in the B and C cohorts; however, the median 50% inhibitory concentration (IC(50) titer) reached by antibody in the plasma of subtype C-infected subjects, overall, was 3.5-fold higher than in the subtype B-infected subjects (P = 0.06). The higher titers of NAbs in the C cohort were associated with viruses having significantly shorter amino acid length (P = 0.002) in the V1 to V4 region of the surface Env glycoprotein, gp120, compared to the B cohort. Despite the potency of the autologous subtype C NAb response, it was not directed against cross-neutralizing epitopes. These data demonstrate that subtype C Envs elicit a potent yet restricted NAb response early in infection that frequently reaches IC(50) titers in excess of 1:1,000 and suggest that clade-specific differences may exist in Env immunogenicity or susceptibility to neutralization.
Acquired Immunodeficiency Syndrome↗
Human leukocyte antigen B58 supertype and human immunodeficiency virus type 1 infection in native Africans.
Human leukocyte antigen (HLA) class I alleles can be grouped into supertypes according to their shared peptide binding properties. We examined alleles of the HLA-B58 supertype (B58s) in treatment-naïve human immunodeficiency virus type 1 (HIV-1)-seropositive Africans (423 Zambians and 202 Rwandans). HLA-B and HLA-C alleles were resolved to four digits by a combination of molecular methods, and their respective associations with outcomes of HIV-1 infection were analyzed by statistical procedures appropriate for continuous or categorical data. The effects of the individual alleles on natural HIV-1 infection were heterogeneous. In HIV-1 subtype C-infected Zambians, the mean viral load (VL) was lower among B*5703 (P = 0.01) or B*5703-Cw*18 (P < 0.001) haplotype carriers and higher among B*5802 (P = 0.02) or B*5802-Cw*0602 (P = 0.03) carriers. The B*5801-Cw*03 haplotype showed an association with low VL (P = 0.05), whereas B*5801 as a whole did not. Rwandans with HIV-1 subtype A infection showed associations of B*5703 and B*5802 with slow (P = 0.06) and rapid (P = 0.003) disease progression, respectively. In neither population were B*1516-B*1517 alleles associated with more favorable responses. Overall, B58s alleles, individually or as part of an HLA-B-HLA-C haplotype, appeared to have a distinctive impact on HIV-1 infection among native Africans. As presently defined, B58s alleles cannot be considered uniformly protective against HIV/AIDS in every population.
Africa↗
Racial and ethnic differences in use of assistive devices for mobility: effect modification by age.
PURPOSE: The authors investigated the extent to which differences in mobility device use existed by race/ethnicity and whether the effects were modified by age. METHOD: Using Phase II of the National Health Interview Survey on Disability, the authors identified 7,148 mobility-impaired adults. Logistic regression models provided estimates of race/ethnicity, adjusting for predictors of device use. RESULTS: Blacks were 1.2 times as likely as non-Hispanic Whites (95% CI: 1.0-1.4) to use devices. Hispanics were 0.78 times less likely to use devices as were non-Hispanic Whites (95% CI 0.65-0.96). Differences were attenuated by age, with a 40% increased likelihood of use attributable to being Black and aged 45 to 75, a 30% increased likelihood attributable to being Hispanic and aged 65 to 75, and a 130% increased likelihood attributable to being Hispanic and older than 75. CONCLUSION: Disentangling the observed patterns in mobility device use will provide direction for development of interventions to promote assistive device use.
Adult↗
Use of complementary therapies during chemotherapy: influence of patients' satisfaction with treatment decision making and the treating oncologist.
The relationship between the use of complementary therapy (CT) and satisfaction with medical treatment decision making and with the treating oncologist was evaluated in a sample of 166 women who were undergoing an initial course of chemotherapy for early-stage breast cancer. At the beginning of chemotherapy, 39% indicated already trying CT and an additional 13% reported planning to try CT. These women mentioned a variety of vitamin, nutritional, herbal, physical, mental, and spiritual approaches. Four months later, when most patients had completed chemotherapy, more than half (53%) reported using CT, with another 8% planning to try it. Regression analysis controlling for psychosocial and medical variables revealed that women who were younger and less satisfied with their treatment decision-making experience were significantly more likely to use CT. When predicting use of CT at the conclusion of treatment, baseline utilization was the greatest predictor, but dissatisfaction with the oncologist was also a significant predictor. These findings suggest that patients who are dissatisfied with their medical care may be more likely to use CT during treatment. Further research is needed to elucidate the relationship between satisfaction with medical decision making and the patient-physician relationship to CT use among cancer patients. The findings also highlight the importance of good patient-physician communication about CT use throughout the cancer treatment experience.
Adult↗
Antigenic conservation and immunogenicity of the HIV coreceptor binding site.
Immunogenic, broadly reactive epitopes of the HIV-1 envelope glycoprotein could serve as important targets of the adaptive humoral immune response in natural infection and, potentially, as components of an acquired immune deficiency syndrome vaccine. However, variability in exposed epitopes and a combination of highly effective envelope-cloaking strategies have made the identification of such epitopes problematic. Here, we show that the chemokine coreceptor binding site of HIV-1 from clade A, B, C, D, F, G, and H and circulating recombinant form (CRF)01, CRF02, and CRF11, elicits high titers of CD4-induced (CD4i) antibody during natural human infection and that these antibodies bind and neutralize viruses as divergent as HIV-2 in the presence of soluble CD4 (sCD4). 178 out of 189 (94%) HIV-1-infected patients had CD4i antibodies that neutralized sCD4-pretreated HIV-2 in titers (50% inhibitory concentration) as high as 1:143,000. CD4i monoclonal antibodies elicited by HIV-1 infection also neutralized HIV-2 pretreated with sCD4, and polyclonal antibodies from HIV-1-infected humans competed specifically with such monoclonal antibodies for binding. In vivo, variants of HIV-1 with spontaneously exposed coreceptor binding surfaces were detected in human plasma; these viruses were neutralized directly by CD4i antibodies. Despite remarkable evolutionary diversity among primate lentiviruses, functional constraints on receptor binding create opportunities for broad humoral immune recognition, which in turn serves to constrain the viral quasispecies.
Amino Acid Sequence↗
Viral dynamics and CD4+ T cell counts in subtype C human immunodeficiency virus type 1-infected individuals from southern Africa.
Defining viral dynamics in natural infection is prognostic of disease progression and could prove to be important for vaccine trial design as viremia may be a likely secondary end point in phase III HIV efficacy trials. There are limited data available on the early course of plasma viral load in subtype C HIV-1 infection in Africa. Plasma viral load and CD4+ T cell counts were monitored in 51 recently infected subjects for 9 months. Individuals were recruited from four southern African countries: Zambia, Malawi, Zimbabwe, and South Africa and the median estimated time from seroconversion was 8.9 months (interquartile range, 5.7-14 months). All were infected with subtype C HIV-1 and median viral loads, measured using branched DNA, ranged from 3.82-4.02 log10 RNA copies/ml from 2-24 months after seroconversion. Viral loads significantly correlated with CD4+ cell counts (r=-0.5, p<0.0001; range, 376-364 cells/mm3) and mathematical modeling defined a median set point of 4.08 log10 (12 143 RNA copies/ml), which was attained approximately 17 months after seroconversion. Comparative measurements using three different viral load platforms (bDNA, Amplicor, and NucliSens) confirmed that viremia in subtype C HIV-1-infected individuals within the first 2 years of infection did not significantly differ from that found in early subtype B infection. In conclusion, the course of plasma viremia, as described in this study, will allow a useful baseline comparator for understanding disease progression in an African setting and may be useful in the design of HIV-1 vaccine trials in southern Africa.
Africa, Southern↗
Predictors of HIV serostatus among HIV discordant couples in Lusaka, Zambia and female antenatal clinic attendants in Kigali, Rwanda.
Clinical manifestations of HIV disease in Africa are nonspecific and easily confused with other endemic diseases. Several studies have compared the prevalence of HIV-related signs and symptoms in infected versus uninfected populations, but little is known about differences in HIV disease manifestations between African men and women across geographic areas. We conducted a cross-sectional study to define predictors of HIV status and assess their differences by gender and country in two African cohorts: 1351 heterosexual couples recruited from a voluntary HIV counseling and testing center in Lusaka, Zambia, and 1458 women recruited from antenatal and pediatric clinics in Kigali, Rwanda. HIV-positive Zambian men and women differed most with respect to prevalence of wasting syndrome (48.1% vs. 35.5%, p < 0.01). Zambian women were more likely to have a disseminated adenopathy than Rwandan women (33.2% vs. 7.8%, p < 0.01) and had a much higher median erythrocyte sedimentation rate (ESR) than either of the two other groups (78 mm/hr vs. 47 mm/hr, p < 0.01). Multivariable logistic regression modeling showed a history of tuberculosis [odds ratio (OR): 2.8-20.7], adenopathy on examination (OR: 4.0-6.3), and an ESR of >65 mm/hr (OR: 3.1-5.9) to be strongly predictive of HIV status in all groups. These screening tools, though highly predictive of HIV infection, were insensitive, as most infected persons were asymptomatic. Given these differences in HIV disease manifestation, screening tools based on signs and symptoms should be adapted accordingly. Additional studies are required to evaluate clinical markers as predictors of HIV disease progression and adjust them according to regional and gender differences.
Adolescent↗
Why is fertility an issue for HIV-infected and at-risk women?
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Africa↗
Novel and promiscuous CTL epitopes in conserved regions of Gag targeted by individuals with early subtype C HIV type 1 infection from southern Africa.
Characterization of optimal CTL epitopes in Gag can provide crucial information for evaluation of candidate vaccines in populations at the epicenter of the HIV-1 epidemic. We screened 38 individuals with recent subtype C HIV-1 infection using overlapping consensus C Gag peptides and hypothesized that unique HLA-restricting alleles in the southern African population would determine novel epitope identity. Seventy-four percent of individuals recognized at least one Gag peptide pool. Ten epitopic regions were identified across p17, p24, and p2p7p1p6, and greater than two-thirds of targeted regions were directed at: TGTEELRSLYNTVATLY (p17, 35%); GPKEPFRDYVDRFFKTLRAEQATQDV (p24, 19%); and RGGKLDKWEKIRLRPGGKKHYMLKHL (p17, 15%). After alignment of these epitopic regions with consensus M and a consensus subtype C sequence from the cohort, it was evident that the regions targeted were highly conserved. Fine epitope mapping revealed that five of nine identified optimal Gag epitopes were novel: HLVWASREL, LVWASRELERF, LYNTVATLY, PFRDYVDRFF, and TLRAEQATQD, and were restricted by unique HLA-Cw*08, HLA-A*30/B*57, HLA-A*29/B*44, and HLA-Cw*03 alleles, respectively. Notably, three of the mapped epitopes were restricted by more than one HLA allele. Although these epitopes were novel and restricted by unique HLA, they overlapped or were embedded within previously described CTL epitopes from subtype B HIV-1 infection. These data emphasize the promiscuous nature of epitope binding and support our hypothesis that HLA diversity between populations can shape fine epitope identity, but may not represent a constraint for universal recognition of Gag in highly conserved domains.
Africa, Southern↗
Is the Vpr R77Q mutation associated with long-term non-progression of HIV infection?
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Disease Progression↗