Effect of BMI and fat mass on HIV disease progression in HIV-infected, antiretroviral treatment-naïve adults in Botswana.

An obesity paradox has been proposed in many conditions including HIV. Studies conducted to investigate obesity and its effect on HIV disease progression have been inconclusive and are lacking for African settings. This study investigated the relationship between overweight/obesity (BMI≥25 kg/m2) and HIV disease progression in HIV+ asymptomatic adults not on antiretroviral treatment (ART) in Botswana over 18 months. A cohort study in asymptomatic, ART-naïve, HIV+ adults included 217 participants, 139 with BMI of 18·0-24·9 kg/m2 and seventy-eight participants with BMI≥25 kg/m2. The primary outcome was time to event (≥25 % decrease in cluster of differentiation 4 (CD4) cell count) during 18 months of follow-up; secondary outcomes were time to event of CD4 cell count<250 cells/µl and AIDS-defining conditions. Proportional survival hazard models were used to compare hazard ratios (HR) on time to events of HIV disease progression over 18 months. Higher baseline BMI was associated with significantly lower risk of an AIDS-defining condition during the follow-up (HR 0·218; 95 % CI 0·068, 0·701; P=0·011). Higher fat mass at baseline was also significantly associated with decreased risk of AIDS-defining conditions during the follow-up (HR 0·855; 95 % CI 0·741, 0·987; P=0·033) and the combined outcome of having CD4 cell count≤250/µl and AIDS-defining conditions, whichever occurred earlier (HR 0·918; 95 % CI 0·847, 0·994; P=0·036). All models were adjusted for covariates. Higher BMI and fat mass among the HIV-infected, ART-naïve participants were associated with slower disease progression. Mechanistic research is needed to evaluate the association between BMI, fat mass and HIV disease progression.

Reduced rate of disease development after HIV-2 infection as compared to HIV-1.

Human immunodeficiency virus type-2 (HIV-2) is a close relative of the prototype acquired immunodeficiency syndrome (AIDS) virus, HIV-1. HIV-2 is biologically similar to HIV-1, but information is lacking concerning clinical outcomes of HIV-2-infected individuals. From 1985 to 1993, a prospective clinical study was conducted in women with HIV-2 and HIV-1 infection to determine and compare rates of disease development. HIV-1-infected women had a 67% probability of AIDS-free survival 5 years after seroconversion in contrast with 100% for HIV-2-infected women. In addition to having significantly less HIV-related disease outcome in HIV-2 enrollees compared to HIV-1 enrollees, the rate of developing abnormal CD4+ lymphocyte counts with HIV-2 infection was also significantly reduced. This natural history study demonstrates that HIV-2 has a reduced virulence compared to HIV-1.

New human T-lymphotropic retrovirus related to simian T-lymphotropic virus type III (STLV-IIIAGM).

This report describes serologic evidence for a virus similar to that known as simian T-lymphotropic virus type III of African Green monkeys (STLV-IIIAGM) infecting apparently healthy people in Senegal, West Africa, and the isolation of virus from these individuals. Serum samples from selected healthy West African people showed unusual serologic profiles when tested with antigens of HTLV-III/LAV, the etiologic agent of AIDS, and of STLV-IIIAGM. The samples reacted strongly with all of the major viral antigens of STLV-IIIAGM but showed variable or no reactivity with the major viral antigens of HTLV-III/LAV by radioimmunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A new human T-lymphotropic virus (HTLV-IV) isolated from these people was grown in vitro and shown to have retroviral type particles, growth characteristics, and major viral proteins similar to those of the STLV-III and HTLV-III/LAV group of retroviruses. The gp120/160, gp32, p64, p55, p53, p24, and p15 proteins precipitated were the same size as and reactive with STLV-IIIAGM proteins. The serologic data suggest that this virus shares more common epitopes with STLV-IIIAGM than with the prototype HTLV-III/LAV that infects people in the United States and Europe. Further study of this virus and of the origin of the HTLV-III/LAV group of viruses may expand our understanding of the human AIDS virus.

Natural protection against HIV-1 infection provided by HIV-2.

Significant differences have been observed in the rates of transmission and disease development in human immunodeficiency virus (HIV) types 1 and 2. Because many HIV-2-infected people remain asymptomatic for prolonged periods, the hypothesis that HIV-2 might protect against subsequent infection by HIV-1 was considered. During a 9-year period in Dakar, Senegal, the seroincidence of both HIV types was measured in a cohort of commercial sex workers. Despite a higher incidence of other sexually transmitted diseases (STDs), HIV-2-infected women had a lower incidence of HIV-1 than did HIV-seronegative women, with a relative risk of 0.32 (P = 0.008). An understanding of the cross-protective mechanisms involved may be directly relevant to HIV-1 vaccine development.

Human T-lymphotropic virus type 4 and the human immunodeficiency virus in West Africa.

A new human T-lymphotropic virus (HTLV-4) was recently described in healthy people from Senegal. This virus has many properties in common with members of the human T-lymphotropic viruses, particularly the human immunodeficiency virus or HIV, the etiologic agent of acquired immune deficiency syndrome (AIDS), but does not appear to be associated with immunodeficiency-related disorders. In the present study, serum samples were obtained from 4248 individuals from six West African countries, including Senegal, Guinea, Guinea Bissau, Mauritania, Burkina Faso, and Ivory Coast. These samples, collected during 1985-1987, were from people categorized as healthy control, sexually active risk, and disease populations. All samples were analyzed for reactivity to HTLV-4 and HIV by radioimmunoprecipitation-sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Evidence for HTLV-4 infection was found in five of the six countries. The seroprevalence varied markedly from country to country. Healthy sexually active individuals in the risk category had the highest levels of HTLV-4 infection compared to individuals in the healthy control category and the disease category, the latter including AIDS patients. The seroprevalence of HIV infection in most of these countries was quite low, although tightly associated with the rare cases of AIDS. The biology of HTLV-4 infection thus differs from that of HIV in Central Africa or the United States and Europe. The presence of these viruses and their different pathogenicities in several countries of West Africa indicate the necessity for serologic assays that will distinguish between them. Further studies of their origin and distribution as well as of their biology will be important in advancing our understanding of AIDS.

HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV.

Heterosexual transmission by vaginal intercourse accounts for most transmission of human immunodeficiency virus-type 1 (HIV-1) in Africa and Asia but is less important in the HIV-1 epidemics of the United States and Western Europe. Epithelial Langerhans' cells (LCs) represent a possible source of initial cell contact for vaginal infection. Fifteen primary isolates of HIV-1 from U.S. homosexuals and 18 HIV-1 isolates from Thailand heterosexuals were evaluated for growth in LCs of U.S. origin. All the viruses from the Thai heterosexuals, which were subtype E, grew more efficiently in the LCs than any of the viruses from the U.S. homosexuals, which are subtype B. These results suggest that LC tropism is associated with the efficiency of heterosexual transmission of HIV.

Lessons from the second AIDS virus, HIV-2.

PIP: Although the clinical signs and symptoms of human immunodeficiency virus (HIV)-2 are similar to those associated with HIV-1 infection, the former virus has a markedly lower perinatal transmission rate and heterosexual infectivity potential. An ongoing cohort study in Senegal, where the disease was first encountered a decade ago, of 136 HIV-2-infected women found an overall incidence of acquired immunodeficiency syndrome of only 0.18/100 person-years in 548 person-years of observation. Moreover, the rate of developing an abnormal CD4 lymphocyte count from the time of infection onward was 1%/year for HIV-2 infected women compared to 10% for HIV-1. In vitro studies of HIV-2 have shown reduced cell killing, less syncytia formation, and slower viral replication compared to HIV-1. It remains unclear whether viral features alone account for the long clinical latency period and different transmission dynamics of HIV-2. An interesting early finding of the Senegalese study is that partial protection from HIV-1 exists in those already infected with HIV-2. Further delineation of the mechanisms involved in this seeming protective effect should be a high research priority given the potential for prevention of the more virulent HIV-1 strain.^ieng

Cost-effective diagnosis of HIV-1 and HIV-2 by recombinant-expressed env peptide (566/996) dot-blot analysis.

OBJECTIVE: To characterize the recombinant env peptides, 566 (HIV-1) and 996 (HIV-2), for their ability to serodiagnose HIV-1 and HIV-2 infection. To develop a cost-effective dot-blot format for these peptides, and to evaluate its performance in a developing country laboratory. DESIGN: The recombinant env peptides were evaluated using a select panel of sera (n = 327) with known serostatus from geographically diverse areas. A dot-blot assay was developed and tested on a second set of immunoblotted sera (n = 331) and further evaluated in the field on a third set of sera (n = 2718) from study populations. METHODS: All sera were evaluated by immunoblot with both HIV-1 and HIV-2 viral lysates. The recombinant env peptides were characterized in immunoblot assay before development of the dot-blot assay. RESULTS: The 566 (HIV-1) peptide showed 100% sensitivity and specificity. The 996 (HIV-2) peptide performed similarly, but showed the presence of HIV-1 cross-reactive epitopes. When the two env peptides were used together, there was high specificity and sensitivity for detecting HIV-positive sera in both immunoblot and dot-blot formats. The dot-blot assay performed in the field showed slightly lower specificity and sensitivity for HIV diagnosis. The relative cost of this assay combined with non-commercial immunoblot confirmation was 10-fold lower than conventional commercial assays. CONCLUSIONS: The 566 and 996 env peptides are appropriate antigens for HIV serotype diagnosis. A dot-blot assay using these peptides may be a useful cost-effective method for HIV diagnosis applicable in developing country laboratories.

HIV-1 and HIV-2 dual infection: lack of HIV-2 provirus correlates with low CD4+ lymphocyte counts.

OBJECTIVE: We conducted this study to genetically characterize dual infection in individuals demonstrating a dual serological profile. METHODS: All subjects were first evaluated by immunoblot for antibody reactivity to the major viral antigens for HIV-1 and HIV-2. Sera were judged to be dual-seropositive if they reacted with strong and equal intensity with the envelope antigens of both HIV-1 and HIV-2 and were confirmed with type-specific recombinant env peptides. We used nested polymerase chain reaction (PCR) to amplify proviral gag and env sequence from peripheral blood mononuclear cell (PBMC) DNA from HIV-1- and HIV-2-infected individuals. Positive amplification was detected after Southern blot hybridization. RESULTS: Plasmid dilution and mixing showed equivalent sensitivity of HIV-1 and HIV-2 primers that was not altered by heterologous target sequences. The DNA PCR showed 100% sensitivity and specificity for detection of monotypic HIV infection. Serologically defined HIV-dual reactives were evaluated by this assay, with 100% detection in female sex workers (21 out of 21), but only 38.5% detection (five out of 13) in hospitalized patients; all being HIV-1 positive only. The lack of HIV-2 proviral signal was significantly correlated with low CD4+ lymphocyte counts (Pvalue = 0.04). CONCLUSION: The results suggest that HIV dual infection may not be a static condition. Levels of HIV-2 may decrease with disease progression or sequester in tissue reservoirs; our results may also suggest that HIV-1 effectively overgrows HIV-2 in the dually exposed host individual.

HIV-2 link to AIDS in West Africa.

To date, very little is known concerning the clinical spectrum of human immunodeficiency virus type 2 (HIV-2) infection, and the question as to whether HIV-2 will ultimately prove to be as pathogenic as human immunodeficiency virus type I (HIV-1) remains, as yet, unanswered. We reviewed the currently available reports of HIV-2 infection to assess what is known about the extent of HIV-2 pathogenicity as it compares to HIV-1 pathogenicity. There is evidence that HIV-2 is associated with AIDS. Most of this evidence, however, comes from descriptive case-report type data that do not meet the basic requirements for defining causality. The most significant problems are the lack of control groups and the absence of a documented temporal relationship with HIV-2 infection preceding the development of AIDS. Comparisons of the epidemiology and disease association between HIV-1 and HIV-2 in Africa may suggest relative pathogenic effects. Although certain comparisons between HIV-2 and HIV-1 are difficult to make, we conclude on the basis of existing data that the pathogenic effects and the natural history of HIV-2 are distinct from those of HIV-1.

Association of immune activation with intravenous heroin use and methadone treatment in HIV-1 seropositive and seronegative subjects.

This study evaluated the effect of continued heroin use during methadone treatment on serum neopterin levels in 40 human immunodeficiency virus (HIV) type 1 seropositive (HIV+) and 70 seronegative (HIV-) intravenous drug users (IVDUs). Persistent drug use, determined by urinary evidence of opiates, was more common in HIV+ than in HIV- IVDUs (p = 0.01). Serum neopterin concentration, an indicator of increased probability of progression to AIDS, was elevated in HIV+ IVDUs, p < 0.0001 (mean 16.0 nmol/L) compared to that of HIV- IVDUs (mean 10.0 nmol/L) and in persistent IV drug users compared with abstainers, p < 0.0001. The effect of drug use and HIV status on serum neopterin was not explained by differences in methadone treatment, age, sex, or total years of i.v. drug use. Neopterin decreased in 25 IVDUs, regardless of HIV serostatus, treated with methadone for an average of 1.5 years.

Neurologic consequences of HTLV-II infection in injection-drug users.

Several case reports have suggested an association between human T-cell lymphotropic virus type II (HTLV-II) infection and chronic neurologic disease. We performed serial neurologic examinations in injection-drug users (IDU), a group known to be at increased risk for HTLV-II infection. At baseline, those infected with HTLV-II alone, human immunodeficiency virus (HIV) alone, or both were significantly more likely to have neurologic disability than uninfected subjects. Longitudinally, HTLV-II infection was independently associated with the development of global neurologic disability and neuropathy, suggesting that HTLV-II causes neurologic disease.

Identification of most frequent HLA class I antigen specificities in Botswana: relevance for HIV vaccine design.

Since the mid-1990s, southern African countries have been experiencing an expansion of human immunodeficiency virus type 1 (HIV-1) infection caused by HIV-1 subtype C. To facilitate the design of an HLA-based HIV vaccine, we studied the distribution of the HLA class I antigen specificities in Botswana, a southern African country with a high prevalence of HIV infection. Botswana's highly efficient health care system and its central geographical location within southern Africa suggests that it might be an appropriate candidate site for future trials of an HLA-based HIV vaccine. Specificities of HLA class I genes have been investigated in DNA samples obtained from 161 persons of Botswana origin by polymerase chain reaction (PCR) with sequence-specific primers. We identified 4 HLA-A, 7 HLA-B, and 5 HLA-C specificities that were observed at high frequencies in the Botswana population: A30, A02, A23, A68, B58, B72, B42, B8, B18, B44, B45, Cw7, Cw2, Cw17, Cw6, and Cw4. HLA-A30, A02, A23, A68, B58, Cw2, Cw4, Cw6, Cw7, and Cw17 were observed at frequencies of more than 10%. The frequency of HLA-A30 was 27.3%. HLA-B58 (17.9%) was the most frequent generic HLA-B type. Other frequent antigen specificities detected for the HLA-B were B72 (9.6%), B42 (9.3%), B8 (7.4%), B18 (7.4%), B44 (7.4%), and B45 (6.4%). Analysis of haplotype frequencies revealed that haplotypes HLA-A30/HLA-B58 (6.7%), A30/B42 (6.1%), A30/B8 (4.1%), A30/B45 (3.2%), and A23/B58 (2.5%) were the most frequent among two-locus haplotypes. The comparison of HIV-positive patients and noninfected controls for HLA class I specificities confirmed the previously described association of A2/A6802 supertype with resistance to HIV. Our study suggested an increased resistance to HIV infection associated with A68 rather than A2. We also found that the generic HLA-B58 type was associated with increased susceptibility to HIV infection. Our findings suggest that the design of an HLA-based HIV vaccine that includes multiple CTL epitopes restricted by identified common HLA class I specificities might target up to 97.5% of the population in Botswana. The results of this study extend the HLA map to a southern African country that has high rates of HIV and also provide a database for the design of an HLA-based HIV vaccine.

Human T-lymphotropic virus type I (HTLV-I)-specific antibodies and cell-free RNA in crevicular fluid-rich saliva from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy.

Despite the likely role of mucosae in human T cell leukemia virus type I (HTLV-I) transmission, little is known about the mucosal immune response to HTLV-I. The present study evaluated the antibody response to HTLV-I in oral mucosa and the value of crevicular fluid rich saliva (CFRS) for diagnosing HTLV-I infection. CFRS and sera from patients with tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM), asymptomatic carriers, and HTLV-I seronegative individuals from Tumaco, Colombia, were analyzed for HTLV-I specific IgG, IgA, and secretory IgA (sIgA). Detection of IgG in CFRS by enzyme-linked immunosorbent assay correlated with its presence in sera for TSP/HAM patients and asymptomatic carriers. IgA and sIgA were more frequently detected in CFRS and sera from TSP/HAM patients than in those from asymptomatic carriers. An HTLV-I pol fragment could be amplified from CFRS by reverse transcriptase-PCR in 3 TSP/HAM patients and one asymptomatic carrier, all of whom had an IgA response in CFRS but not in sera. The more frequent detection of IgA and sIgA in sera and CFRS of TSP/HAM patients suggests increased viral replication. Further, the association of viral RNA in CFRS with a local IgA response may signify rounds of viral replication in the oral cavity.

Clinical care issues for women living with HIV and AIDS in the United States.

As the number of women infected with HIV in the United States continues to increase, the medical community is faced with the challenge of providing adequate and appropriate care to them. This paper reviews key questions concerning the state of knowledge on the epidemiology, biology, and clinical care of women living with HIV and AIDS in the United States. Because heterosexual transmission accounts for a growing number of cases among women, biological factors and cofactors that may enhance women's susceptibility to HIV infection are also reviewed. HIV-related gynecological issues are presented separately to evaluate whether gynecological complications are distinct in HIV-uninfected and HIV-infected women. Questions of whether there are sex-specific differences in the efficacy and adverse effects of new antiviral agents are discussed. In addition, significant gaps are highlighted that still exist in our understanding of both the effects of HIV and HIV-related drugs upon pregnancy. Finally, the psychiatric stresses and complications that affect women living with HIV and AIDS are also discussed. In each section of this review, gaps in our knowledge of these issues are identified. To properly address these disparities in knowledge, not only do efforts to gather sex-specific biomedical data need to be more exacting, but there is a distinct need to conduct more sex-specific research concerning HIV.

Intrapatient variability of the human immunodeficiency virus type 2 envelope V3 loop.

Studies of HIV-2 infection have shown lower rates of sexual and perinatal transmission and a prolonged incubation period to AIDS as compared to HIV-1. To evaluate the role of genetic variation in HIV pathogenesis, we studied intrapatient variability in the V3 loop of the HIV-2 envelope gene over time in five seropositive individuals. Proviral sequences derived from uncultured PBMC DNA (n = 102) demonstrated an average sequence heterogeneity within a sample of 1.4% (0-4.1%). This was significantly lower than the V3 sequence heterogeneity observed in HIV-1, which can be as high as 6.1%. In HIV-2-seropositive healthy patients the average intrapatient nucleotide variability rate was 0.6% compared to 2.0% in patients with clinical AIDS. The lower rate of variability between HIV-2 and HIV-1 is compatible with differences in transmission and pathogenesis of these two related viruses.

HIV type 1 A/J recombinant with a pronounced pol gene mosaicism.

A nearly full-length genome sequence of a novel HIV-1 A/J recombinant with a complex structure of the pol gene has been analyzed. This virus was isolated in 1998 from a 35-year-old female from Botswana. The virus demonstrated a dual pattern for CXCR4/CCR5 coreceptor utilization. Using short-term enrichment of the donor's PBMCs, the 98BW21 isolate was long-range amplified, cloned, and sequenced. The sequence of the clone 98BW21.17 spanned 9103 bp from the PBS site to the U5 region of the 3' LTR. The phylogenetic relationship of the 98BW21.17 clone to HIV-1 sequences represented by M, N, and O groups and A-K subtypes of the M group was examined across the entire viral genome. The 98BW21.17 clone demonstrated a unique phylogenetic topology clustering within subtype A or subtype J reference sequences. However, the subtype origin of two regions within the pol gene (p51 RT and integrase) could not be identified. Recombination patterns of the 98BW21.17 clone were different from known AGJ/AGIJ-type viruses such as isolates BFP90 and 95ML84. This study demonstrated the existence and replication competence of a new dual-tropic X4/R5 recombinant form of HIV-1 on the subtype J backbone. The nucleotide sequence of the 98BW21.17 clone was submitted to GenBank under accession number AF192135.

Antibodies to the HIV type 2 core protein p26 and Vpx: association with disease progression.

A longitudinal cohort study was conducted to define the prevalence and temporal pattern of antibody response to the HIV-2 virion-associated proteins p26gag and Vpx. One hundred and forty-one asymptomatic HIV-2-infected women were enrolled, and followed for up to 11 years. Eighty-one percent of the subjects had antibodies to p26, and 51% to Vpx; response to these two antigens was not correlated. The response to both proteins was determined early in infection, and remained stable over time. The absence of antibodies to p26 was a highly significant predictor of CDC category IV HIV-related disease (p < 0.01) in both univariate and multivariate analysis. Antibody response to Vpx alone was not associated with disease progression. However, those individuals lacking anti-p26 antibodies, and with anti-Vpx antibodies, were six times more likely to be classified as CDC category IV by the end of the study (p < 0.01). This represents the first identification of virus-specific serological markers for HIV-2-related disease progression.

Clinical, hematologic, and immunologic cross-sectional evaluation of individuals exposed to human immunodeficiency virus type-2 (HIV-2).

We studied the clinical status and certain hematologic and immunologic parameters in healthy prostitutes from Dakar, Senegal who were seropositive for antibodies to human immunodeficiency virus type-2 (HIV-2). Generalized lymphadenopathy and clinical signs or symptoms similar to those which are seen with human immunodeficiency virus type-1 (HIV-1) infection were not present. Comparison to seronegative prostitutes and minor surgery control patients were made and significant elevations were seen in T8 lymphocytes (p = .03), IgG (p = .0001), and beta 2-microglobulin (p = .03). The mean T4 lymphocyte count in seropositive prostitutes was lower than in seronegative prostitutes (757 vs. 1179, p = .15), but this difference was not statistically significant and appeared to be correlated with age. No significant differences were noted between the seronegative and seropositive prostitutes in lymphocyte stimulation studies to certain mitogens. Antilymphocyte antibodies above background were not present in either population. We conclude that HIV-2 is a sexually transmitted agent that produces immunologic alterations consistent with a persistent viral infection. HIV-2 seropositive prostitutes studied to date do not show clinical signs of immune suppression, as has been described with HIV-1 infection. The pathogenic potential of HIV-2 appears to differ from that of HIV-1, the etiologic agent of the AIDS pandemic.

Bronchoscopic and radiologic features of Kaposi's sarcoma involving the respiratory system.

In a group of 61 patients admitted to New England Deaconess Hospital, Boston, with a diagnosis of acquired immune deficiency syndrome (AIDS), 25 were found to have Kaposi's sarcoma involving the skin and mucous membranes. Of these 25 patients, eight had lesions involving the respiratory system. Radiographically, patients with Kaposi's sarcoma had hilar and mediastinal adenopathy with perihilar parenchymal infiltration which progressed to diffuse bilateral infiltrates over a period of months. This pattern and the tempo of its evolution were distinctly different from the diffuse infiltrates seen in patients with Pneumocystis carinii pneumonia. Bronchoscopy was performed in seven of the eight patients, revealing characteristic lesions of Kaposi's sarcoma in the airways. We propose that parenchymal pulmonary Kaposi's sarcoma can be strongly suspected in a patient with AIDS who has the following features: a characteristic radiologic pattern; endobronchial Kaposi's sarcoma at bronchoscopy; and no evidence of opportunistic infection. In this subset of patients, further diagnostic intervention such as open lung biopsy, a procedure with potential morbidity in these ill individuals, may be unnecessary.