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.

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.

Xenotropic viruses: murine leukemia viruses associated with NIH Swiss, NZB, and other mouse strains.

Murine leukemia virus activity is present in tissues from NIH Swiss and other mouse strains after cocultivation with nonvirus-yielding rat cells transformed by Harvey sarcoma virus. The resulting pseudotype sarcoma virus has the same type-specific coat as the virus previously isolated from New Zealand black (NZB) mice, and, like the NZB virus, it is unable to infect mouse cells. The results show that this NZB type virus is endogenous in other strains of mice and is xenotropic; that is, it grows only in cells foreign to the host. This is the first clear demonstration that NIH Swiss mice also carry indigenous infectious murine leukemia virus.

Demonstration of biological activity of a murine leukemia virus of New Zealand black mice.

Although New Zealand Black mouse embryo and adult tissues show evidence of murine leukemia viral particles and antigens, efforts to demonstrate biological activity of a murine leukemia virus by standard methods have proved negative. Cocultivation of tissues of these mice with non-virus-yielding hamster cells transformed by Moloney sarcoma virus, however, has resulted in the rescue of a pseudotype sarcoma virus, presumably carrying the New Zealand Black mouse leukemia virus coat. This virus has an unusual host restriction, producing foci of cell alteration only in rat cells.

Murine sarcoma virus: the question of defectiveness.

Infection of mouse and rat cells by the murine sarcoma virus (Moloney isolate) showed two-hit kinetics for focus production in mouse cells but one-hit kinetics in rat cells. Antiserum added to cultures after infection suppressed focus formation in mouse cells but not in rat cells. These studies suggest that, in rat cells infected with murine sarcoma virus, leukemina virus is not needed for focus formation and that these foci result from proliferation of the transformed rat cell; in mouse cells, on the other hand, leukemia virus is needed as "helper," and focus formation requires spread of virus. The term "defectiveness" then, if used, should not be applied to RNA tumor viruses without qualification for the viral function studied and the cell system employed.

Biologic features of HIV-1 that correlate with virulence in the host.

Individuals infected with the human immunodeficiency virus type 1 (HIV-1) may be asymptomatic or have AIDS-related complex or the acquired immuno deficiency syndrome (AIDS). Little is known about the factors that influence progression of infection to AIDS. In this study of isolates of HIV-1 obtained at intervals during the infection of four individuals, the development of disease was found to be correlated with the emergence of HIV-1 variants that were more cytopathic in vitro as the disease progressed and that replicated more efficiently in a wide variety of different human cells. The biologic properties of HIV-1 in vitro thus appear to reflect its virulence in the host. Further studies of such sequentially isolated viruses may lead to the identification of viral genes that govern pathogenesis.

Persistent noncytopathic infection of normal human T lymphocytes with AIDS-associated retrovirus.

Infection of normal peripheral blood T cells by the acquired immune deficiency syndrome (AIDS)-associated retrovirus (ARV) was evaluated in long-term cultures of helper-inducer T cells (T4 cells). Cells that were inoculated with ARV and maintained in medium supplemented with interleukin-2 remained productively infected with this virus for more than 4 months in culture, although they showed no cytopathic effects characteristic of acute ARV infection. The presence of replicating virus was demonstrated by reverse transcriptase activity of culture fluids and by viral antigens and budding particles detected on cells by immunofluorescence and electron microscopy. Virus produced in these cultures remained infectious and could induce cytopathic effects and viral antigens in uninfected lymphoid cells. The finding that normal lymphocytes may be productively infected by an AIDS retrovirus in the absence of cell death suggests that a range of biologic effects may occur after infection in vivo.

Differential effects of nef on HIV replication: implications for viral pathogenesis in the host.

Stable lymphoid cell lines expressing the human immunodeficiency virus type 1 (HIV-1) nef gene product, p27, were established. The presence of p27 in the lymphoid cells suppressed replication of some strains of both HIV-1 and HIV-2. This observation indicates that nef could be important in the establishment of HIV latency. In contrast, fast replicating and highly cytopathic HIV-1 isolates recovered from patients with advanced disease states were not affected by the negative effect of nef present in these lymphoid cell lines. This lack of response to nef appears to constitute another viral feature that correlates with disease progression. Thus, manipulating expression of the nef gene in vivo might influence pathogenesis in the host.

The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells.

Antibodies that enhance human immunodeficiency virus (HIV) infectivity have been found in the blood of infected individuals and in infected or immunized animals. These findings raise serious concern for the development of a safe vaccine against acquired immunodeficiency syndrome. To address the in vivo relevance and mechanism of this phenomenon, antibody-dependent enhancement of HIV infectivity in peripheral blood macrophages, lymphocytes, and human fibroblastoid cells was studied. Neither Leu3a, a monoclonal antibody directed against the CD4 receptor, nor soluble recombinant CD4 even at high concentrations prevented this enhancement. The addition of monoclonal antibody to the Fc receptor III (anti-FcRIII), but not of antibodies that react with FcRI or FcRII, inhibited HIV type 1 and HIV type 2 enhancement in peripheral blood macrophages. Although enhancement of HIV infection in CD4+ lymphocytes could not be blocked by anti-FcRIII, it was inhibited by the addition of human immunoglobulin G aggregates. The results indicate that the FcRIII receptor on human macrophages and possibly another Fc receptor on human CD4+ lymphocytes mediate antibody-dependent enhancement of HIV infectivity and that this phenomenon proceeds through a mechanism independent of the CD4 protein.

AIDS retrovirus (ARV-2) clone replicates in transfected human and animal fibroblasts.

A molecular clone of the AIDS-associated retrovirus (ARV-2) was transfected into human T lymphocyte and monocyte cell lines as well as mouse, mink, monkey, and human fibroblast lines. A replicating virus with cytopathic and biologic properties of ARV-2 was recovered from all the cell lines. The animal and human fibroblast cells are resistant to direct infection by ARV, and in these experiments virus production in the fibroblast lines, especially mouse, was reduced compared to human lymphocytes. However, human fibroblasts were more permissive to virus expression than mouse cells. These results show that, whereas the primary block to ARV infection in certain cells may occur at the cell surface, intracellular mechanisms can also participate in controlling virus replication. The results have relevance to vaccine development and encourage further work with modified molecular clones to examine regions of the ARV genome necessary for cytopathology and replication.

CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication.

Lymphocytes bearing the CD8 marker were shown to suppress replication of human immunodeficiency virus (HIV) in peripheral blood mononuclear cells. The effect was dose-dependent and most apparent with autologous lymphocytes; it did not appear to be mediated by a cytotoxic response. This suppression of HIV replication could be demonstrated by the addition of CD8+ cells at the initiation of virus production as well as after several weeks of virus replication by cultured cells. The observations suggest a potential approach to therapy in which autologous CD8 lymphocytes could be administered to individuals to inhibit HIV replication and perhaps progression of disease.

An AIDS-like condition induced in baboons by HIV-2.

Six baboons (Papio cynocephalus) were intravenously inoculated with the human immunodeficiency virus-type 2 (HIV-2) strain HIV-2UC2. All seroconverted within 6 weeks after inoculation; five animals became persistently infected. Four developed lymphadenopathy, and three of the animals had CD4+ T cell loss within 18 to 24 months after inoculation. One of these baboons, showing severe clinical symptoms, showed at necropsy widespread dissemination of virus with follicular depletion in the lymph nodes, extensive fibromatosis involving lymphoid and nonlymphoid tissues, and lymphocytic interstitial pneumonitis. Another animal is cachectic and exhibited lymphoid follicular lysis and fibrous skin lesions. Other baboons inoculated with a second strain, HIV-2UC14, have shown evidence of persistent infection. HIV-2 infection of baboons provides a valuable animal model for studying HIV persistence and pathogenesis and for evaluating approaches to antiviral therapies.

Characterization of a noncytopathic HIV-2 strain with unusual effects on CD4 expression.

A new isolate of the human immunodeficiency virus type 2, designated HIV-2UC1, was recovered from an Ivory Coast patient with normal lymphocyte numbers who died with neurologic symptoms. Like some HIV-1 isolates, HIV-2UC1 grows rapidly to high titers in human peripheral blood lymphocytes and macrophages and has a differential ability to productively infect established human cell lines of lymphocytic and monocytic origin. Moreover, infection with this isolate also appears to involve the CD4 antigen. However, unlike other HIV isolates, HIV-2UC1 does not cause cytopathic effects in susceptible T cells nor does it lead to loss of CD4 antigen expression on the cell surface. These results indicate that HIV-2 may be found in individuals with neurologic symptoms and that the biological characteristics of this heterogeneous subgroup can differ from those typical of HIV-1.

Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS.

Infectious retroviruses have been detected in 22 of 45 randomly selected patients with acquired immune deficiency syndrome (AIDS) and in other individuals from San Francisco. The AIDS-associated retroviruses (ARV) studied in detail had a type D morphology, Mg2+-dependent reverse transcriptase, and cytopathic effects on lymphocytes. The viruses can be propagated in an established adult human T cell line, HUT-78. They cross-react with antiserum to the lymphadenopathy-associated retrovirus isolated from AIDS patients in France. Antibodies to ARV were found in all 86 AIDS patients and in a high percentage of 88 other homosexual men in San Francisco. This observation indicates the widespread presence of these lymphocytopathic retroviruses and their close association with AIDS.

Rapid loss of CD4+ T cells in human-PBL-SCID mice by noncytopathic HIV isolates.

Human immunodeficiency virus (HIV) isolates differ in cell tropism, replication, pathogenicity, and syncytial induction in vitro. CD4+ T cells were enumerated in severe combined immunodeficient mice transplanted with human peripheral blood leukocytes (hu-PBL-SCID mice) and infected with HIV isolates with different in vitro cytopathicity. Two noncytopathic, macrophage-tropic strains, HIV-1SF162 and HIV-2UC1, induced extensive CD4+ T cell depletion, whereas HIV-1SF33, which is highly cytopathic for T cells in vitro, caused little CD4+ T cell depletion at equivalent virus burden. In vitro cytopathicity assays therefore do not predict CD4 depletion in the hu-PBL-SCID model.

Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2).

The nucleotide sequence of molecular clones of DNA from a retrovirus, ARV-2, associated with the acquired immune deficiency syndrome (AIDS) was determined. Proviral DNA of ARV-2 (9737 base pairs) has long terminal repeat structures (636 base pairs) and long open reading frames encoding gag (506 codons), pol (1003 codons), and env (863 codons) genes. Two additional open reading frames were identified. Significant amino acid homology with several other retroviruses was noted in the predicted product of gag and pol, but ARV-2 was as closely related to murine and avian retroviruses as it was to human T-cell leukemia viruses (HTLV-I and HTLV-II). By means of an SV-40 vector in transfected simian cells, the cloned gag and env genes of ARV-2 were shown to express viral proteins.

CD8+ cell anti-HIV activity correlates with the clinical state of the infected individual.

The extent of antiviral activity exhibited in vitro by CD8+lymphocytes from individuals infected by HIV-1 correlates significantly with their clinical status. CD8+ lymphocytes from asymptomatic subjects were found to inhibit HIV-1 replication by 90% or greater at effector/target (E/T) ratios ranging from as low as 0.05 to 0.25. CD8+ cells from 17 of 19 (89%) of these subjects suppressed replication at an E/T ratio of 0.10 or less. CD8+ lymphocytes from symptomatic patients (non-AIDS) inhibited HIV-1 replication at E/T ratios ranging from 0.05 to 1.0, and CD8+ cells from 8 of 13 (62%) required ratios greater than 0.10. As a group, patients with AIDS exhibited the lowest degree of anti-HIV activity with their CD8+ lymphocytes. The effective range of E/T ratios from AIDS patients was 0.10-2.0, and 9 of 10 (90%) required E/T ratios greater than 0.25. This anti-HIV activity exhibited by CD8+ cells also correlated significantly with the subject's peripheral blood CD4+ cell count. The relative extent of CD8+ cell anti-HIV-1 activity was not found dependent on variations in the CD4+ target cells and viruses used. These findings suggest that the decreased CD8+ cell antiviral activity is related to progression to disease in HIV-infected individuals.

Identification of human immunodeficiency virus (HIV) envelope type-specific T helper cells in an HIV-infected individual.

Two T helper cell clones recognizing the gp 120 envelope protein of HIV were generated from the peripheral blood of a healthy seropositive individual. These cells were type specific as they proliferated and produced IL 2 when stimulated by an epitope in the amino-terminal half of gp 120 of HIVSF2, but not by a similar region of HIVZr6, a Zairian HIV-1 isolate. These two viruses differ by 26% in the deduced amino sequence of the gp 120 protein. Moreover, the antigenic site(s) recognized by the cloned T cells are distinct from those recognized by envelope-specific antibodies. These observations have important implications for the development and use of anti-HIV vaccines.

Do beta-chemokines have clinical relevance in HIV infection?

The role of beta-chemokines in HIV infection was evaluated. The kinetics of regulated upon activation of normal T cell expressed and secreted, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein 1beta production by stimulated T lymphocytes did not differ substantially between HIV-infected (asymptomatic and with AIDS) and uninfected subjects. Maximal production of these beta-chemokines by activated peripheral blood cells was higher in the infected individuals than in uninfected individuals, but no significant difference was observed between healthy infected subjects and AIDS patients. Evaluation of the effect of HIV replication on beta-chemokine production indicated that acute infection of CD4+ T cells with non-syncytia-inducing (NSI) viruses generally increased beta-chemokine production two to eightfold, whereas with SI strains, it led to decreased production. The sensitivity of an individual's virus to beta-chemokine-mediated inhibition correlated with the NSI virus phenotype and a healthy clinical state. 50% of the AIDS patients, however, had NSI viruses that were sensitive to beta-chemokines. Finally, anti-beta-chemokine-neutralizing antibodies caused a more rapid release of HIV by CD4+ T cells naturally infected by NSI, but not SI, viruses indicating that endogenously produced chemokines can affect HIV production in culture. These findings suggest that beta-chemokines may affect HIV replication when an NSI virus is involved, but provide little evidence that they substantially influence HIV infection and pathogenesis.