The human immunodefiency virus (HIV) uses the human CD4 glycoprotein as a receptor for infection of susceptible cells. Cells expressing a series of mutated forms of the CD4 gene have shown a variability in their ability to support replication of three HIV type 1 (HIV-1) and three HIV-2 strains. Moreover, when different stages of virus production were examined by a variety of assays, a consistent delay was observed in all cell lines containing CD4 mutants compared with those with intact full-length CD4. Cells expressing the CD4.415 mutant (modified at the serine 415 corresponding to a phosphorylation site of the cytoplasmic domain) showed only a minimal effect on virus replication. Cells expressing CD4.403 and CD4.401 mutants (lacking the whole cytoplasmic domain) manifested a moderate delay in production of virus progeny. The most substantial effect on HIV replication was observed in cells expressing a chimeric hybrid containing sequences corresponding to the first 177 residues of the N-terminal CD4 fused to CD8 sequences encoding the hinge, transmembrane, and cytoplasmic domains of the human CD8. Furthermore, in a cell-to-cell contact assay, fusion was absent when the CD4 proximal membrane domain was replaced by the CD8 counterpart. In addition, a strong correlation between the down-modulation of the surface CD4 and HIV expression was observed. These observations suggest that in addition to the known binding region, other domains of CD4 could play an important role in regulating HIV entry of cells.

Seven HIV-2 isolates recovered from peripheral blood mononuclear cells (PBMC) of patients from the Ivory Coast have been biologically characterized. All seven strains replicated well in primary human lymphocyte and macrophage cultures and in established human T cell lines. They showed differences in infectivity and replicating ability in primary PBMC cultures from chimpanzees, rhesus macaques, and baboons. Moreover, variations in levels of virus replication in PBMC from 13 seronegative donors were observed. Four strains (UC2, UC3, UC7, and UC8) were highly cytopathic and caused extensive surface CD4 antigen depletion in acutely infected PBMC and SupT1 cells. Two strains (UC1 and UC6) showed minimal or no cytopathology, no CD4 down-modulation, and much lower levels of virus protein expression in SupTl cells. These findings reflect the heterogeneity of HIV-2 strains and suggest that these biological properties could influence pathogenesis in the host.

To define the target antigens for antibody-dependent cellular cytotoxicity (ADCC), assays were performed using affinity-purified human immunoglobulin (Ig) or polyclonal rabbit sera directed against specific proteins of HIV. ADCC was not found using affinity-purified anti-core (p25) human Ig or sera obtained from rabbits hyper-immunized with recombinant p25. However, when affinity-purified human Ig or rabbit antisera specific for the envelope glycoproteins, gp120 or gp41, were used in ADCC assays, killing of HIV-infected cells was observed. These results indicate that antibodies in the infected individual that mediate ADCC are directed against both the gp120 and gp41 HIV envelope proteins and not against the viral core protein.

Article de synthese presentant les aspects biologiques et pathologiques de l'infection par le virus d'immunodeficience humaine qui provoque des dysfonctions du systeme immunitaire, des desordres neurologiques et une enteropathologie

HIV research in the past year has elucidated many questions relevant to strategies for treatment and control. For instance, there is a greater understanding of the diversity of HIV isolates as well as the wide range of potential cells sensitive to infection. The search for a safe, effective vaccine now calls for more caution in the light of the discovery of neutralization-resistant variants and antibody-mediated enhancement of infection. Efforts to control HIV must take into account the various mechanisms of virus entry into host cells, and the processes involved in cytopathic effects. Moreover, the role of cells of the mononuclear phagocyte system as reservoirs for HIV particles should be recognized. Together with new information about cytokine induction of HIV, the concept of latent infection of monocytes and macrophages has profound implications for virus persistence and dissemination, especially in the seronegative individual. While many factors about HIV have been uncovered in the past year, several questions remain unanswered and new ones have arisen. For instance, in how many ways does the virus kill in host cell? What causes latency and why does it occur in some but not all hosts? How can virus-filled macrophage vesicles be reached by therapeutic agents or prevented from releasing HIV? What surveillance mechanisms allow some productively infected hosts (cells as well as individuals) to survive beyond expectation? These and other questions should provoke future research on this presently complex and challenging pathogen.

The human immunodeficiency virus (HIV) type 1 displays a high degree of genetic variation, especially in the glycoprotein (gp120) domain of the envelope gene. To determine whether this genomic heterogeneity leads to the expression of independent HIV subtypes, 12 sera from HIV type 1 antibody-positive individuals were tested for their ability to neutralize 20 HIV isolates of various origins. Four distinct HIV subtypes with different sensitivity to serum neutralization were identified. These results suggest that a finite number of HIV subtypes exist and that the combined use of selected HIV isolates representing several subtypes may be necessary for the development of an effective vaccine.

A new isolate of the human immunodeficiency virus type 2, designated HIV-2 UC1 , was recovered from an Ivory Coast patient with normal lymphocyte numbers who died with neurologic symptoms. Like some HIV-1 isolates, HIV-2 UC1 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-2 UC1 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.

Tonsillar B lymphocytes from an asymptomatic individual infected with HIV were transformed with EBV. A cloned lymphoblastoid cell line was obtained that secreted human mAb (IgG4 subtype) against the known gag gene products of 55,000 and 25,000 Da and a protein of 40,000 Da. The latter p40 protein appears to be a HIV gag-related gene product that is also recognized immunologically by individuals infected by HIV. Although the mAb detects infection of cells by different HIV isolates, it does not neutralize HIV or show activity in an antibody-dependent cytotoxicity assay.

Two distinct human immunodeficiency viruses, HIV-1SF480 and HIV-2UC2 were isolated simultaneously from the blood of an Ivory Coast patient with AIDS. The HIV subtypes were segregated by their differential ability to infect established human cell lines and by the cell surface expression of type-specific viral antigens. The viruses could be distinguished by both immunoblot and Southern blot analyses. The results indicate that an individual can be infected by both HIV subtypes.

We cultured bronchoalveolar lavage fluid for the human immunodeficiency virus (HIV) from 23 consecutive patients with acquired immunodeficiency syndrome (AIDS) and pulmonary symptoms. We also included a nonconsecutive AIDS patient with recent worsening of respiratory symptoms who had had lymphocytic interstitial pneumonitis (LIP) diagnosed six months earlier. Infectious HIV was present in the cellular fraction from two of the 23 consecutive patients and in the patient with LIP. No virus was isolated from the cell-free portion of the centrifuged fluids. The patients from whom HIV was cultured were not distinguishable from other patients by clinical, radiographic, or laboratory data, and their subsequent course did not appear to differ. One patient with a positive HIV culture had organizing pneumonia without evidence of LIP at autopsy three weeks after lavage. This study demonstrates that HIV can be cultured from cells obtained by bronchoalveolar lavage and suggests that its presence is not associated with a single specific pulmonary histologic pattern.

Isolates of HIV showed distinct differences in the ability to replicate in continuous human hematopoietic cell lines. Moreover, although all PMC cultures obtained from healthy individuals could be infected with HIV, considerable variation in the amount of virus released from different PMC cultures was observed. These biological properties of HIV could not be correlated with clinical state, binding properties of the virus isolates to target cells, or differences in target cell CD4 antigen expression. Some isolates of HIV that could not directly infect the HUT-78 cell line showed productive infection when PMC infected with these viruses were added to this human T cell line. These observations emphasize the importance of cell to cell contact in the spread of virus. The results demonstrate for the first time the differences in the host range specificity of HIV isolates in several individual PMC cultures, and indicate that the optimal isolation of HIV is achieved with normal human PMC rather than established human cell lines.

The AIDS-associated retrovirus (ARV) was isolated from vaginal and/or cervical secretions from 4 out of 8 women whose sera contained antibodies to the virus. The quantity of virus recovered initially was so low that identification of ARV was accomplished only after passage of the isolates to cultured mitogen-stimulated normal human peripheral blood mononuclear cells. The results indicate that the vaginal canal under certain conditions could be a source of transmission of ARV.