Dynamics of viral replication in infants with vertically acquired human immunodeficiency virus type 1 infection

About one-third of vertically HIV-1 infected infants develop AIDS within the first months of life; the remainder show slower disease progression. We investigated the relationship between the pattern of HIV-1 replication early in life and disease outcome in eleven infected infants sequentially studied from birth. Viral load in cells and plasma was measured by highly sensitive competitive PCR-based methods. Although all infants showed an increase in the indices of viral replication within their first weeks of life, three distinct patterns emerged: (a) a rapid increase in plasma viral RNA and cell-associated proviral DNA during the first 4-6 wk, reaching high steady state levels (> 1,000 HIV-1 copies/10(5) PBMC and > 1,000,000 RNA copies/ml plasma) within 2-3 mo of age; (b) a similar initial rapid increase in viral load, followed by a 2.5-50-fold decline in viral levels; (c) a significantly lower (> 10-fold) viral increase during the first 4-6 wk of age. All infants displaying the first pattern developed early AIDS, while infants with slower clinical progression exhibited the second or third pattern. These findings demonstrate that the pattern of viral replication and clearance in the first 2-3 mo of life is strictly correlated with, and predictive of disease evolution in vertically infected infants.     

Serum levels of human immunodeficiency virus type 1 (HIV-1) RNA after seroconversion: a predictor of long-term mortality in HIV infection

A cohort of 79 homosexual men with documented dates of human immunodeficiency virus type 1 (HIV-1) seroconversion and baseline CD4 cell counts of > or = 500/microL were followed for up to 11.5 years. HIV-1 RNA was measured from stored sera obtained a median of 7 months after the estimated seroconversion date. AIDS progression and mortality among the men were studied, stratified by median baseline levels of HIV-1 RNA. AIDS progression rates at 11.5 years were 69% and 34%, respectively, among those with higher versus lower than median baseline virus loads (> or = 3040 copies/mL; P = .002), and mortality rates were 61% and 27%, respectively (P = .003). Survival curves continued to diverge throughout the 11.5 years, suggesting that the future clinical course of HIV-1 infection may already be determined at the earliest phases of disease. Initiation of definitive treatment very early in HIV-1 infection may be essential.     

In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease

Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (HIV)-caused disease. The emergence of resistance to the current anti-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an HIV-protease inhibitor. Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-psi (CHOH)]2 (P9941), failed to yield a stock of virus with a resistance phenotype. However, variants of the virus with 6- to 8-fold reduced sensitivity to P9941 were selected by using a combination of plaque assay and endpoint titration. Genetic analysis and computer modeling of the variant proteases revealed a single change in the codon for amino acid 82 (Val-->Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.     

T cell responses in coinfection with Onchocerca volvulus and the human immunodeficiency virus type 1

Onchocerca volvulus and the human immunodeficiency virus (HIV) are two immunocompromising infectious agents of major public health concern in Uganda. To examine the effect of coinfection with O. volvulus and HIV on cellular immune responses, lymphocyte proliferative responses and cytokine production of peripheral blood mononuclear cells (PBMC) from persons infected with O. volvulus with and without HIV type 1 infection were compared. Proliferation of PBMC to PHA and tuberculin (PPD) in coinfection was less (P = 0.08, P < 0.01) than in O. volvulus infection. O. volvulus extract stimulated lymphocyte proliferation in microfilaria-negative and HIV-negative O. volvulus infection while only an inconspicuous response was observed in microfilaria-negative coinfection. After stimulation of PBMC with PPD, the production of interferon-gamma (IFN-gamma), interleukin (IL)-4 and IL-5-demonstrated in O. volvulus infection-were reduced in coinfection with HIV (P < 0.01). While both groups failed to produce IFN-gamma in response to O. volvulus extract, only O. volvulus infected persons generated pronounced IL-5 and low IL-4 levels (0.01 > P = 0.02). The cellular immune responses in coinfection suggested an HIV-related lack of specific reactivity to O. volvulus antigen and impairment of IL-4 and IL-5 production in addition to the lack of IFN-gamma response on antigenic stimulation.     

Prophylaxis after occupational exposure to human immunodeficiency virus (HIV)

Reasons for seeking consultation among health care workers due to potential or supposed risk of HIV infection were analyzed. From August 1990 till July 1996 41 health care providers were consulted including: 22 nurses, 1 student of nursing college, 3 midwives, 4 laboratory workers and 7 physicians (surgeons and gynaecologist). Type of exposure to HIV and applying of safety precautions were evaluated in each case. In 10 cases the offer of postexposure prophylaxis with zidovudine was accepted (6 nurses, 1 student of nursing college, 3 surgeons). Exposure to HIV was described as: needlestick immediately after it was used in a HIV/AIDS patient, injury with a surgical needle while operating on an HIV infected blood. In the remaining cases the fear of HIV infection was due to work without protective gloves (nurses, laboratory workers), performing surgery on HIV (+) patient, (surgeons, nurses) or short-time contact of HIV infected blood with undamaged skin (nurses). Following conclusions can be drawn from our study: 1. Health care workers undertake safety precautions only when they are informed about HIV seropositivity of the patient. 2. Patients whose HIV serologic status is not known are considered not to create health risk for medical staff. 3. The level of knowledge of health care workers about risk of acquiring HIV infection, lack of risk and ways of diminishing the risk is poor. 4. None of followed health care workers was HIV-seropositive after occupational exposure to HIV.     

Depressive syndromes and symptoms in subjects with human immunodeficiency virus (HIV) infection

The association between the infection produced by the human immunodeficiency virus (HIV) and syndromal or subsyndromal depression has been the topic of several studies in recent years. The results of the WHO Neuropsychiatric AIDS Study, conducted in the five geographical areas predominantly affected by the HIV epidemic, suggest that the symptomatic stages of HIV infection are associated with an increased prevalence of depressive symptoms, and, at least in some contexts in which the spreading of the infection is more recent and the social rejection of HIV-seropositive subjects is harsher, may also be associated with an increased prevalence of a syndromal diagnosis of depression.     

Progressive multifocal leukoencephalopathy presenting as human immunodeficiency virus type 1 (HIV)-associated dementia

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder of the CNS that usually causes hemiparesis or hemianopsia. Dementia occurs in combination with other neurologic abnormalities. We report a human immunodeficiency virus type 1 (HIV)-infected man whose only manifestation of proven PML was dementia that was clinically indistinguishable from HIV-associated dementia.     

Abnormalities of measles antibody response in human immunodeficiency virus type 1 (HIV-1) infection

The finding that severe measles occurs in immunized as well as nonimmunized human immunodeficiency virus (HIV)-infected individuals suggests that both immunologic memory and the initial response to measles may be impaired by HIV infection. That the initial response is affected was supported by the finding that post-measles immunization titers of HIV-infected babies were significantly lower (p = 0.01) than those of normal babies. Poor immunologic memory was evidenced in HIV-infected children by lower titers than in normal children (p < 0.001) and by a continuing decline in measles antibody that was not arrested by reimmunization. Impaired memory appeared to be associated with defective avidity maturation. HIV-infected babies and infants or children had a significantly lower avidity index (AI) than age-matched normal children (p < 0.01). HIV-infected adults, who were infected with HIV following infection with measles, did not have AI values significantly different from normal adults (p = 0.18) but had significantly greater values than did HIV-infected babies and children (p < 0.01). Thus, in contrast to infants and children who were infected with HIV before measles immunization, the adult immune response to measles was less affected.     

Primary infection by type 1 human immunodeficiency virus: diagnosis and prognosis

Primary infection by type 1 human immunodeficiency virus (HIV) is symptomatic in about 70% of cases. The acute illness is a mononucleosis-like syndrome with characteristics such as mucosal ulcerations. The duration and severity of the symptoms appear to be related to the prognosis. After reviewing the most frequent signs and symptoms of primary HIV infection, we report different prognostic studies which examined the association between the acute illness and the progression of HIV disease.     

Inhibition of human immunodeficiency virus type 1 replication by a Tat-activated, transduced interferon gene: targeted expression to human immunodeficiency virus type 1-infected cells

We have examined the feasibility of using interferon (IFN) gene transfer as a novel approach to anti-human immunodeficiency virus type 1 (HIV-1) therapy in this study. To limit expression of a transduced HIV-1 long terminal repeat (LTR)-IFNA2 (the new approved nomenclature for IFN genes is used throughout this article) hybrid gene to the HIV-1-infected cells, HIV-1 LTR was modified. Deletion of the NF-kappa B elements of the HIV-1 LTR significantly inhibited Tat-mediated transactivation in T-cell lines, as well as in a monocyte line, U937. Replacement of the NF-kappa B elements in the HIV-1 LTR by a DNA fragment derived from the 5'-flanking region of IFN-stimulated gene 15 (ISG15), containing the IFN-stimulated response element, partially restored Tat-mediated activation of LTR in T cells as well as in monocytes. Insertion of this chimeric promoter (ISG15 LTR) upstream of the human IFNA2 gene directed high levels of IFN synthesis in Tat-expressing cells, while this promoter was not responsive to tumor necrosis factor alpha-mediated activation. ISG15-LTR-IFN hybrid gene inserted into the retrovirus vector was transduced into Jurkat and U937 cells. Selected transfected clones produced low levels of IFN A (IFNA) constitutively, and their abilities to express interleukin-2 and interleukin-2 receptor upon stimulation with phytohemagglutinin and phorbol myristate acetate were retained. Enhancement of IFNA synthesis observed upon HIV-1 infection resulted in significant inhibition of HIV-1 replication for a period of at least 30 days. Virus isolated from IFNA-producing cells was able to replicate in the U937 cells but did not replicate efficiently in U937 cells transduced with the IFNA gene. These results suggest that targeting IFN synthesis to HIV-1-infected cells is an attainable goal and that autocrine IFN synthesis results in a long-lasting and permanent suppression of HIV-1 replication.     

Risk for human immunodeficiency virus (HIV) infection among persons with severe mental illnesses

Individuals diagnosed with a severe mental illness are at significantly enhanced risk for infection with the human immunodeficiency virus (HIV). To better understand elevated seroprevalence in this population, we review the research literature that has investigated HIV-related risk behavior among adults who have a severe and persistent mental illness. This review indicates that 54%-74% of adults report that they have been sexually active in the last year with approximately one third reporting two or more partners. Among those who were sexually active, condom use was inconsistent. A significant minority (4%-35%) of adults also reported a history of injection drug use. Overall, the data indicate that the severely mentally ill engage regularly in practices known to involve increased risk for HIV transmission. We introduce and modify Fisher and Fisher's (1992) theoretical model to organize the possible determinants of HIV-related risk taking among severely mentally ill adults, and encourage use of this model in the design of behavioral epidemiological and risk reduction studies. We also identify several methodological challenges to HIV-related research, including problems associated with the use of self-report measures; diagnostic imprecision; and participant recruitment and retention.     

Allergic diseases and infection with human immunodeficiency virus (HIV)-AIDS in pediatric patients

During an infection with human immunodeficiency virus (HIV) the immune system is deregulated, even before real immunodeficiency, lymphopenia and AIDS occur. The immunologic alterations that have been described are a differentiation of a T-lymphocyte subclass, Th1 to Th0. Immunologic stimulation of these Th0 cells afterwards, makes them mature into Th2 cells. This causes a imbalance between the Th1 and Th2 cells, in favor of the second group. The clinical expression of this imbalance is an elevated risk of HIV-seropositive patients for allergies and for autoimmune disease, specially those autoimmune disease in which the production of autoantibodies prevails. Sometimes of differential diagnosis with systemic lupus erythematosus is difficult. There has been describes a major prevalence of allergic diseases, especially allergic rhinitis, in adult patients infected by HIV. Reports in pediatric patients are still sporadic, and the prevalence of allergies in children infected with HIV-AIDS is unknown. Only after recognizing the allergic nature of some symptoms, the treatment will be complete, reducing morbidity and infectious complications.     

Bacteremia and fungemia in patients with advanced human immunodeficiency virus (HIV) infection in Taiwan

To understand the etiology and clinical outcome of bacterial and fungal sepsis in patients with advanced human immunodeficiency virus (HIV) infection in Taiwan, we conducted a prospective study of nonmycobacterial bacteremia and fungemia in HIV-infected patients with fever who were admitted to a university hospital in Taiwan during a 42-month period. Of 210 patients, 41 (19.5%) had a total of 52 episodes of sepsis due to nonmycobacterial bacteria or fungi, or both (15.5% of 336 episodes of fever). All but one patient had acquired immunodeficiency syndrome (AIDS), and the mean CD4 lymphocyte count was 29/microL (range, 0-321/microL). A total of 57 pathogens (39 bacteria and 18 fungi) were isolated from blood; polymicrobial sepsis due to both bacteria and fungi occurred in four episodes. Nontyphoid Salmonella (NTS) was the most common cause of community-acquired bacteremia (24/30, 80%). Staphylococcus aureus bacteremia was diagnosed in three episodes while Streptococcus pneumoniae bacteremia was found in only one. Cryptococcus neoformans was the most common cause of fungemia and was responsible for 12 episodes, while fungemia due to Penicillium marneffei and Histoplasma capsulatum, two emerging fungi in Taiwan, were diagnosed in four cases and one case, respectively. Nine episodes, eight of bacteremia and one of candidemia, were nosocomial. The overall in-hospital mortality was 29%, and nosocomial sepsis was associated with a higher mortality rate (56%, p = 0.02). The mean duration of survival after recovery from initial sepsis was 426 days. We conclude that NTS bacteremia was the most common cause of sepsis in patients with advanced HIV infection in Taiwan and clinicians caring for such patients should watch for emerging fungal infections. Nosocomial sepsis was associated with a high mortality rate. The mean survival duration after recovery from sepsis of our patients was short.     

Mutations in the human immunodeficiency virus type 1 integrase D,D(35)E motif do not eliminate provirus formation

The core domain of human immunodeficiency virus type 1 (HIV-1) integrase (IN) contains a D,D(35)E motif, named for the phylogenetically conserved glutamic acid and aspartic acid residues and the invariant 35 amino acid spacing between the second and third acidic residues. Each acidic residue of the D,D(35)E motif is independently essential for the 3'-processing and strand transfer activities of purified HIV-1 IN protein. Using a replication-defective viral genome with a hygromycin selectable marker, we recently reported that a mutation at any of the three residues of the D,D(35)E motif produces a 10(3)- to 10(4)-fold reduction in infectious titer compared with virus encoding wild-type IN (A. D. Leavitt et al., J. Virol. 70:721-728. 1996). The infectious titer, as measured by the number of hygromycin-resistant colonies formed following infection of cells in culture, was less than a few hundred colonies per microg of p24. To understand the mechanism by which the mutant virions conferred hygromycin resistance, we characterized the integrated viral DNA in cells infected with virus encoding mutations at each of the three residues of the D,D(35)E motif. We found the integrated viral DNA to be colinear with the incoming viral genome. DNA sequencing of the junctions between integrated viral DNA and host DNA showed that (i) the characteristic 5-bp direct repeat of host DNA flanking the HIV-1 provirus was not maintained, (ii) integration often produced a deletion of host DNA, (iii) integration sometimes occurred without the viral DNA first undergoing 3'-processing, (iv) integration sites showed a strong bias for a G residue immediately adjacent to the conserved viral CA dinucleotide, and (v) mutations at each of the residues of the D,D(35)E motif produced essentially identical phenotypes. We conclude that mutations at any of the three acidic residues of the conserved D,D(35)E motif so severely impair IN activity that most, if not all, integration events by virus encoding such mutations are not IN mediated. IN-independent provirus formation may have implications for anti-IN therapeutic agents that target the IN active site.