HIV-related symptoms and patient clusters among Chileans living with HIV.

Identifying both Human immunodeficiency virus (HIV)-related and co-morbid symptoms experienced by people living with HIV (PLWH) who are receiving antiretroviral therapy (ART) treatment is a major challenge for healthcare providers globally. Yet, little research to date has examined the symptoms of illness experienced by PLWH including patients living in Central and South American. To address this gap, this study was designed to identify symptoms of HIV by socio-demographic and/or clinical characteristics among Chilean patients living with the virus. A convenience sample of 209 Chilean PLWH was recruited from an outpatient clinic in Santiago, Chile. A structured interview was used to elicit socio-demographic information and HIV symptoms status. Additional clinical information was obtained through a review of the participants' medical records. Results show that patients' most commonly reported HIV-related symptoms were fear/worries (66%), anxiety (52%), gas/bloating (50%), and thirst (50%). Multivariate analysis revealed a positive association between the number of reported HIV-related symptoms and number of years living with HIV. Having completed college was negatively associated with number of symptoms. Latent class analysis indicated that PLWH in the sample who had completed college were two times more likely to experience a mild intensity of HIV-related symptoms than their lesser educated counterparts. Similarly, logistic regression revealed that college-educated PLWH were twice as likely to be classified in the subgroup reporting mild intensity of symptoms than those who lacked a college degree. Overall, the study's results reveal that many Chilean PLWH, even those with high CD4 counts and low or undetectable viral loads, are not symptom free. The findings point to the need for clinicians to tailor a plan of care for individuals living with HIV that is based on their symptomatology.

Virus-host interactions in HIV pathogenesis: directions for therapy.

The challenge of controlling HIV infection involves an understanding of the heterogeneity of the virus, its wide cellular host range, its primary routes of transmission, and the immunologic and intrinsic cellular factors that can prevent its transmission and replication. Identification of HIV-infected individuals who have survived more than 10 years without signs of the infection and without therapy encourages studies examining the natural mechanisms for resistance to infection and disease. Within the immune system, emphasis should be given to the innate or natural response that appears within minutes of the infection and offers the optimal time for controlling HIV. All these parameters in HIV pathogenesis underline the information needed to develop optimal anti-HIV therapies and an effective AIDS vaccine.

CD8+ cell noncytotoxic antiviral response in long-term HIV-1 infected former blood donors in China.

Most of the HIV-infected long term survivors show strong CD8+ cell noncytotoxic antiviral response (CNAR) that plays as an important factor for maintaining the relative healthy state of infected individuals. HIV infected former blood donors (FBDs) in Anhui, China are the unique population that considered infected by the same or a related HIV strain by the same exposure route, and is better to be studied for viral and host immunological factors associated with disease progression, such as CNAR. We examined CNAR in 63 asymptomatic untreated HIV infected FBDs with different CD4+ cell counts and plasma viral loads. The average CD8+ : CD4+ cell ratio to reach 90% suppression of HIV replication in the groups with CD4+ cell counts of >500, 300-500 and <300 cells/microl were 0.85 : 1, 1.47 : 1 and 1.88 : 1 respectively (P<0.0001). The average CD8+ : CD4+ cell ratio to reach 90% suppression of HIV replication was 1.07 : 1 and 1.66 : 1 in the group with plasma viral load of <30,000 and >30,000 RNA copy/ml respectively (P=0.0002). The results indicated that CNAR activity in long-term HIV-1 infected FBDs correlates directly with CD4+ cell counts, and correlates reversely with plasma viral loads. Our findings in long term infected FBDs confirm the clinical relevancy of CNAR and suggest that CNAR could be an additional marker to help determine the optimal time for starting therapy in HIV infected person.

Association of educational attainment with HIV risk in African American active injection drug users.

This study explored the association between educational attainment and HIV/AIDS risk among African American active injection drug users (IDUs) in Chicago, US. Using snowball sampling techniques, 813 African American active IDUs were recruited for semi-structured interviewing and HIV counseling, testing and partner notification. Logistic regression examined the relationship between level of education attained (three categories: less than high school; equivalent to high school; and greater than high school) and HIV risk behaviors (12 unsafe sex and drug-related practices) and HIV serostatus (positive or negative). Compared with the reference category (less than high school education), those with education equal to high school were less likely to share water, p = 0.044, OR = 0.70 (95%CI: 0.50-0.99). Compared with the reference category, those with education greater than high school were less likely to receive money for sex, p = 0.048, OR = 0.62 (95%CI: 0.38-0.99); share needles with person having HIV or AIDS, p = 0.015, OR = 0.58 (95%CI: 0.37-0.90); and test positive for HIV, p = 0.027, OR = 0.58 (95%CI: 0.36-0.94). The significant associations found between educational attainment and certain HIV risk behaviors and HIV serostatus have implications for tailoring HIV prevention efforts for less educated African American IDUs.

HIV pathogenesis: knowledge gained after two decades of research.

Great progress has been made in our understanding of HIV since its initial discovery about 20 years ago. The ability of HIV to infect CD4+ lymphocytes and a wide variety of other cells in the body is appreciated, as is its role in immunologic, gastrointestinal, and brain disorders. HIV enters cells via the CD4 molecule, chemokine co-receptors (CXCR4, CCR5), and other cell-surface proteins. Several accessory virus-associated genes (e.g., Rev, Tat, Nef) have uncovered unique pathways that can also be observed in normal cells. Recently, the discovery of natural cellular resistant factors (APOBEC3G and TRIM5a) has provided avenues for novel antiviral therapies. Studies of long-term survivors have given insight into immune responses that control HIV and can prevent infection. Neutralizing antibodies and CD8+ cell cytotoxic responses, as well as plasmacytoid dendritic cells and CD8+ cell non-cytotoxic antiviral responses, are adaptive and innate immune activities mediating this anti-HIV effect. HIV vaccine studies have indicated that conventional approaches do not work against this integrated intracellular parasite. While much has been learned about HIV, more details are needed about its infection cycle and its pathologic effects in the body. The past 20 years have yielded important information on HIV/AIDS that should lead to effective anti-HIV therapies and a vaccine.

Influence of religiosity on HIV risk behaviors in active injection drug users.

Previous studies have shown a positive relationship between religiosity and the practice or adoption of protective health behaviors, including reduction of illicit drug use among hard-core injecting drug users (IDUs). The purpose of this study was to examine the role of religiosity in predicting HIV high-risk drug and sexual practices among a sample of IDUs in Chicago, USA. We hypothesized that high religiosity would be associated with a lower likelihood of IDUs engaging in risky behaviors for HIV transmission. Snowball sampling techniques were used to recruit 1,095 active IDUs for HIV testing, counseling and partner notification. Data were analyzed from 880 subjects who self-identified with one of three religions, Christianity, Islam or Judaism. Logistic regression was used to examine the relationship between religiosity (based on self-reports of personal strength of religious belief: very strong; somewhat strong; not at all), independent of specific religion, and HIV risk behaviors (defined as 12 unsafe sex- and drug-related practices) as well as HIV serostatus. Contrary to our hypothesis, subjects with stronger religiosity were more likely to engage in four risk behaviors related to sharing injection paraphernalia. Compared to those who self-reported having no religiosity, subjects who stated that their lives were strongly influenced by religious beliefs were significantly more likely to share injection outfits, cookers, cotton and water. The association of certain HIV risk behaviors with higher religiosity has implications for HIV prevention and warrants further research to explore IDUs' interpretation of religious teachings and the role of religious education in HIV prevention programs.

Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infection.

In chronically HIV infected individuals, a number of functional B cell abnormalities have been described. However, the immediate changes that occur in the B cell compartment following viral exposure and how they affect the long-term course of infection are not well understood. We report the longitudinal analysis of B cell repertoires during early infection in untreated and treated individuals receiving highly active antiretroviral therapy (HAART). Analysis was based on IgG heavy chain gene utilization and CDR3 length measurement and relationship with CD4/CD8 counts, viral load, and total serum IgG, and anti-HIV antibodies levels. Repertoires were assessed at baseline and at weeks 2, 4, 12, 24, and 72 after initiation of therapy. The findings indicate a stable peripheral B cell repertoire during the first 72 weeks following infection, particularly in the HAART treated patients. A modest association between B cell repertoire integrity and viremia levels as well as treatment was detected.

Effect of IL-2 therapy on CD8+ cell noncytotoxic anti-HIV response during primary HIV-1 infection.

Early treatment intervention during human immunodeficiency virus (HIV) infection is a strategy aimed to preserve and/or enhance the developing anti-HIV immune responses. We report the effect of highly active antiretroviral therapy (HAART) combined with intermittent subcutaneous doses of Interleukin 2 (IL-2) on CD8(+) cell noncytotoxic anti-HIV responses (CNAR), as well as on viral loads and CD4(+) cell/CD8(+) cell numbers in subjects with primary HIV-1 infection. Twenty-four patients received HAART, 24 received a combination of HAART plus IL-2, and 12 elected no-therapy. In comparison to HAART alone, IL-2 treatment led to significant increases in CD4(+) cell numbers through week 48 of the study. No effect was observed on viral loads or the CD8(+) cell population. The first cycle of IL-2 enhanced CNAR; later cycles showed no substantial effect. This study suggests that HAART combined with IL-2 could provide an immunologic benefit in the treatment of early HIV infection.

Decreased HIV-specific CD4 T cell proliferation in long-term HIV-infected individuals on antiretroviral therapy.

The effect of highly active antiretroviral therapy (HAART) on HIV-specific CD4 T cell proliferation in long-term HIV-infected individuals was studied. Subjects receiving treatment for over a year were compared with individuals not receiving therapy. The absolute number of HIV-specific memory CD4 T cells proliferating in response to HIV antigen was substantially higher in untreated subjects than in those on HAART. A decrease in HIV-specific memory CD4 T cells could explain the rebound in HIV replication after the termination of HAART.

Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients.

Natural interferon-alpha producing cells (IPCs) are a newly characterized blood cell type, which is the major source of type I interferons in antiviral innate immune responses. The relationship between the number of circulating IPCs, HIV disease progression, and the occurrence of HIV-related complications was investigated. The study of 25 healthy donors and 54 HIV-infected subjects demonstrated a direct correlation between blood IPC number, interferon-alpha production, and clinical state of HIV-infected subjects. Asymptomatic long-term survivors had increased IPC number and function relative to uninfected controls and infected individuals with progressive disease. IPC numbers were markedly reduced in AIDS patients developing opportunistic infections and cancer. A negative correlation was found between the IPC number in the blood and the HIV viral load, suggesting that IPCs are important in controlling HIV replication. This study provides the first evidence that IPCs are being affected during the course of HIV infection and suggests that these cells can play a vital role in the protection against opportunistic pathogens and cancer. (Blood. 2001;98:906-912)

The importance of the innate immune system in controlling HIV infection and disease.

The innate immune system is the first line of defense against invading pathogens and is particularly important in warding off bacterial and viral infections presenting at the mucosal cell surface. From this primitive immune response, the more sophisticated adaptive immune system was derived. Despite nearly two decades of research directed at inducing adaptive immune responses to HIV, no successful immunological therapy or vaccine has been developed. On the basis of recent observations, it is suggested that instead emphasis should now be placed on the alternative arm of the immune system, the innate immune response. Novel approaches should be developed to elicit this rapidly responding immune activity in HIV infection.

Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Longitudinal analysis of T-cell receptor gene use by CD8(+) T cells in early human immunodeficiency virus infection in patients receiving highly active antiretroviral therapy.

The effects of early antiretroviral therapy on the peripheral CD8(+) T-cell population were assessed by sequentially determining the T-cell receptor (TCR) repertoire complexity in a cohort of 15 individuals recently diagnosed with human immunodeficiency virus infection. Analysis was based on quantitative TCR variable B gene (TCRBV) usage and complementary-determining region 3 length assessment. Repertories were assessed at baseline and at weeks 2, 4, 12, 24, and 72 after initiation of therapy. Early administration of highly active antiretroviral therapy has a positive effect on the preservation and homeostasis of the CD8(+) cell repertoire. Nevertheless, differences from average baseline and control TCR profiles and initial development of repertoire perturbations were observed. The findings suggest that additional therapeutic protocols will be required during primary infection to significantly prevent long-term erosion of the T-cell-mediated immune response.

Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection.

Recent advances in the ability to detect people at the early stages of HIV infection now permit the initiation of antiretroviral treatment before the full complement of antiviral immune responses has evolved. However, the influence of early treatment interventions on the developing anti-HIV immune response is unknown. This study investigates the impact of standard highly active antiretroviral therapy (HAART) during the primary stages of HIV infection on the plasma HIV-1 RNA level, CD4(+) and CD8(+) lymphocyte counts, and the CD8(+) cell anti-HIV response. Individuals treated with HAART within 6 months of infection showed dramatic and rapid reductions in HIV-1 RNA levels along with modest increases in CD4(+) cell number and decreases in CD8(+) cell numbers. A significant reduction in the level of CD8(+) cell noncytotoxic suppression of HIV replication was observed over time in most participants receiving HAART. Importantly, those individuals choosing not to receive therapy maintained low but detectable HIV-1 RNA levels and showed no reduction in their CD8(+) cell antiviral response. These results suggest that either continued antigenic challenge is required to sustain CD8(+) cell-mediated anti-HIV activity, or that HAART has some inhibitory effect on this important immunologic function during the early stages of infection.

The nuclear factor kappa B and Spl binding sites do not appear to be involved in virus suppression by CD8 T lymphocytes.

CD8 T lymphocytes suppress primate lentivirus replication in a non-cytotoxic manner. This antiviral activity, mediated by a CD8 cell antiviral factor (CAF), involves an arrest in viral transcription. Present studies indicate that the CD8 T cell non-cytotoxic antiviral activity and CAF inhibit the replication of an SIV mutant virus lacking the nuclear factor kappa B (NF-kappaB) and Spl binding domains. The results strongly suggest that the NF-B and Spl binding sites are not involved in virus suppression by CD8 T lymphocytes.

Baboons as an animal model for human immunodeficiency virus pathogenesis and vaccine development.

Baboons (Papio cynocephalus) provide a valuable animal model for the study of human immunodeficiency virus (HIV) pathogenesis because HIV-2 infection of baboons causes a chronic viral disease that progresses over several years before clinical signs of acquired immunodeficiency syndrome (AIDS) appear. Since HIV-2-infected baboons develop a chronic viral infection, insights into the immuno-biology of viral latency, clinical stages of disease, virus infection of lymphatic tissue and HIV transmission can be gained using this animal model. The development of an AIDS-like disease in baboons is viral isolate and baboon subspecies dependent. Thus, viral virulence factors and host resistance can be studied as well as the mechanisms of innate and acquired immunity. The control of virus infection is dependent upon cytotoxic and non-cytotoxic antiviral activity of CD8+ T cells. In this regard, some of the HIV-2-infected baboons develop potent antiviral cellular immune responses that have a similar magnitude to that found in HIV-1-infected long-term survivors (or non-progressors). In our laboratory, baboons have been used to study DNA vaccine strategies using new cationic liposome formulations and granulocyte macrophage-colony stimulating factor and B7-2 as genetic adjuvants. The results demonstrate the value of using baboons as an animal model of AIDS pathogenesis and vaccine development.

Emery-Dreifuss muscular dystrophy: anatomical-clinical correlation (case report).

We report on a man that had weakness of humeroperoneal distribution associated with limited range of motion of the cervical spine and elbows since he was 5 years old. At age 26 he developed tachycardia episodes. A complex arrhythmia was discovered, and a nodal ablation was done with a cardiac pacemaker implanted. The patient had an arrhythmia and sudden death followed this. Emery-Dreifuss muscular dystrophy is a rare recessive X-linked muscular disorder where mixed patterns in electromyography and muscle histology (neurogenic and/or myopathic) have caused nosological confusion. The autopsy findings are here described and correlated to the clinical features in an attempt to better understand the ambiguous findings concerning the process etiology.

Genetic analysis of viral variants selected in transmission of human immunodeficiency viruses to newborns.

Our previous studies have indicated that HIV transmission from infected mothers to infants occurs with viruses showing rapid kinetics of replication, and either resistance to maternal neutralizing antibodies or sensitivity to enhancing antibodies. The genotypic patterns that result in these and other phenotypic viral characteristics may provide clues to the selection pressures exerted during this mode of transmission. For this reason, DNA sequences of the envelope gene (env) were determined for viral isolates obtained from seropositive women who were mothers of either infected or uninfected infants. Sequences of viruses isolated early in life from the infected newborns were also determined, such that diversity both within isolates and between maternal and infant isolates could be assessed. Among isolates obtained from mothers of uninfected infants, the V3 region of env demonstrated a higher degree of heterogeneity than those from mothers of infected infants. Similar to the viruses obtained from the mothers of infected infants, the infant-derived viral sequences were relatively homogeneous. Finally, the reactivity of maternal plasma with infant-derived HIV isolates, whether via neutralizing or enhancing antibodies, appeared to predict the distribution of viral sequences in the infant isolates. These data suggest that selective pressure on HIV-1 during transmission or growth in the infected infant may be mediated by biologic and/or immunologic processes.

The restricted cellular host range of human herpesvirus 8.

DESIGN: A selection of primary and transformed cell types were evaluated for their susceptibility to infection with human herpesvirus 8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus. METHODS: Sources of HHV-8 included Kaposi's sarcoma lesion punch biopsies that were either cocultured directly with target cells or that were first cocultured with human lymphocytes to derive HHV-8-containing fluids that were inoculated onto target cells. HHV-8 was also obtained from primary effusion lymphoma-derived cell lines. Techniques to detect infection included the PCR, immunofluorescence assays and in situ hybridization. RESULTS: Susceptible cells included human umbilical cord blood mononuclear cells (UCMC), adult CD19 B cells, macrophages and certain endothelial cells of human and animal origin, including some that are transformed with human papilloma virus type 16 E6 and E7 genes. The infection of lymphocytes did not yield established lymphoblastoid cell lines (LCL) and virus infection persisted for only 4-7 days. However, long-term HHV-8 infection of UCMC could be achieved by coinfection with Epstein-Barr virus. HHV-8 could also infect UCMC LCL recently derived by Epstein-Barr virus transformation, but long-established LCL could not be infected with HHV-8. CONCLUSIONS: These data provide further biological evidence in cell culture for the limited cellular host range of HHV-8 to CD19 B cells, macrophages, and certain endothelial cells.