Cytomegalovirus (CMV) DNA Load Is an Independent Predictor of CMV Disease and Survival in Advanced AIDS

The impact of cytomegalovirus (CMV) on human immunodeficiency virus type 1 (HIV-1) disease progression has been controversial. In this study, we sought to determine if CMV viral load is independent of HIV-1 viral load in predicting CMV disease and survival. Our findings indicate that in patients with advanced AIDS, CMV DNA load is an independent marker of CMV disease and survival and is more predictive than HIV-1 RNA load. Moreover, patients who respond to preemptive therapy with oral ganciclovir, with resulting undetectable levels of CMV DNA, in their plasma, have a significantly lower risk of developing CMV disease and higher rates of survival, despite stable or increasing HIV-1 RNA loads. These data provide support for CMV as an independent risk factor for mortality in persons with advanced AIDS and further suggest that effective preemptive therapy for CMV can improve patient survival rates.     

Pulmonary complications of AIDS: a clinical strategy.

Infectious and noninfectious forms of pulmonary disease are the most common complications of acquired immune deficiency syndrome (AIDS), and many are amenable to treatment. We describe the clinical and radiologic features of the most common causes of lung disease in AIDS patients and review the drugs available for treatment. In addition, we provide a strategy for the clinical assessment and management of patients with human immunodeficiency virus infection who have lung infiltrates.     

Racial and other characteristics of human T cell leukemia/lymphoma (HTLV-I) and AIDS (HTLV-III) in Trinidad.

Adult T cell leukaemia/lymphoma was first recognised as a clinical entity in southwest Japan. Subsequently the Caribbean has been found to be another area where the disease is endemic, and sporadic cases have been identified in different parts of the world. The human T cell leukaemia/lymphoma virus (HTLV-I) is causally related to adult T cell leukaemia/lymphoma. A subgroup of HTLV, designated HTLV-III, has recently been isolated from many patients with the acquired immunodeficiency syndrome (AIDS) and preAIDS, and there is now evidence that this variant is the primary cause of AIDS. This is the first report from Trinidad to describe 12 cases of adult T cell leukaemia/lymphoma and 14 of AIDS. All were in patients of African descent. No cases were seen in subjects of East Indian descent, who, like those of African descent, comprise as much as 40% of the population. West Indians of African descent may have increased susceptibility to infection with both HTLV-I and HTLV-III.     

HIV-1 at 25

In 1981, the acquired immunodeficiency syndrome (AIDS) appeared insidiously and mystified doctors and scientists alike. No one could have predicted then that it would become, arguably, the worst plague in human history. Today, 33 million persons are living with infection by the human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, while another 25 million have already died of this disease.     

Convergent evolution within the V3 loop domain of human immunodeficiency virus type 1 in association with disease progression.

Phylogenetic analysis was used to study in vivo genetic variation of the V3 region of human immunodeficiency virus type 1 in relation to disease progression in six infants with vertically acquired human immunodeficiency virus type 1 infection. Nucleotide sequences from each infant formed a monophyletic group with similar average branch lengths separating the sets of sequences. In contrast to the star-shaped phylogeny characteristic of interinfant viral evolution, the shape of the phylogeny formed by sequences from the infants who developed AIDS tended to be linear. A computer program, DISTRATE, was written to analyze changes in DNA distance values over time. For the six infants, the rate of divergence from the initial variant was inversely correlated with CD4 cell counts averaged over the first 11 to 15 months of life (r = -0.87, P = 0.024). To uncover evolutionary relationships that might be dictated by protein structure and function, tree-building methods were applied to inferred amino acid sequences. Trees constructed from the full-length protein fragment (92 amino acids) showed that viruses from each infant formed a monophyletic group. Unexpectedly, V3 loop protein sequences (35 amino acids) that were found at later time points from the two infants who developed AIDS clustered together. Furthermore, these sequences uniquely shared amino acids that have been shown to confer a T-cell line tropic phenotype. The evolutionary pattern suggests that viruses from these infants with AIDS acquired similar and possibly more virulent phenotypes.     

Murine acquired immunodeficiency syndrome (MAIDS): an animal model to study the AIDS pathogenesis

Murine AIDS (MAIDS) is a disease that shows many similarities with human AIDS. Several immunological parameters of the disease have been analyzed and genetic studies have mapped a gene (or genes) of resistance in the H-2 complex and shown that the genetic background of the mouse can significantly modify some features of the disease. The etiologic agent of MAIDS is a defective murine leukemia virus that seems able to induce disease in the absence of virus replication. This defective virus induces proliferation of its target cells and the cell expansion was found to be oligoclonal, thus suggesting that the immunodeficiency observed in these mice is a paraneoplastic syndrome. The excellent response of MAIDS mice to antineoplastic agents is consistent with this notion. This animal model has already been useful in stimulating the emergence of novel questions and the formulation of new hypotheses about human AIDS, namely about the role of defective HIV, the role of HIV replication in the progression of the disease, and the importance to identify the target cells of HIV in vivo. Although MAIDS and AIDS are not identical and are induced by retroviruses of different classes, the availability of such a model in an easily accessible small animal species, whose genetics is very sophisticated, may be instrumental in understanding the pathogenesis of AIDS if some of the cellular and molecular affected pathways are common in both diseases.     

Viral etiologies of AIDS: facts and hypotheses

All the epidemiological features suggest that the acquired immunodeficiency syndrome (AIDS) is caused by a single transmissible agent and surely a virus. First, cytomegalovirus, Epstein-Barr virus and hepatitis B virus have been proposed as possible etiological agents of AIDS. A direct link between ubiquitous viruses and the occurrence of the disease has been discarded. At present time, etiological researches provide evidence that retroviruses are the best candidates for the etiology of AIDS. These agents could be directly responsible of the profound suppression of the cell-mediated immunity observed in patients with AIDS. Two human retroviruses are now proposed: human T-cell leukemia virus (HTLV) or lymphadenopathy associated virus (LAV). Moreover simian AIDS (SAIDS) occurred spontaneously at several primate centers in USA; a retrovirus partially related to Mason Pfizer monkey virus appears to be the etiologic agent of SAIDS.     

The French are different. French and American medicine in the context of AIDS.

Medicine has often been approached as a thing apart from culture, as a uniform Western science. Within the past 10 years, we have begun to recognize that medicine is a system of beliefs and practices intrinsically linked to its larger sociocultural context. Still, it is generally perceived as uniform across North America and Western Europe. My recent research on French and American medical perspectives on the acquired immunodeficiency syndrome (AIDS) challenges this view by exploring differences in the structure of health care, the physician-patient relationship, and the conceptualizations of disease, particularly AIDS. These differences are not specific to AIDS, but the disease serves to exemplify them and to act as a medium for expressing what makes French and American medicine distinct. Global epidemics such as AIDS require both international response and cross-cultural understanding.     

The Vancouver Lymphadenopathy-AIDS Study: 5. Antecedent behavioural,clinical and laboratory findings in patients with AIDS and HIV-seropositive controls.

In a group of homosexual men in Vancouver studied prospectively since November 1982, 26 cases of acquired immune deficiency syndrome (AIDS) have arisen. To identify behavioural, clinical and laboratory findings that might predict the development of AIDS in people with antibody to human immunodeficiency virus (HIV), we compared data for 25 patients with AIDS with corresponding data for 80 controls serologically positive for HIV selected from the cohort. The clinical and laboratory data for the patients with AIDS preceded the diagnosis of the syndrome by a mean of 17.5 months. The controls had been both seropositive and AIDS-free for a mean of 16.7 months after acquisition of their data. We detected significant differences between the patients with AIDS and the controls in IgG and IgA levels, absolute number of helper T cells and ratio of helper to suppressor T cells but not in lifetime number of male sexual partners, frequency of receptive anal intercourse or receptive fisting, illicit drug use or history of infectious disease. We also detected an increased risk of AIDS among those who had an elevated number of sexual contacts in AIDS-endemic areas in the 5 years before enrollment. A history of increased early sexual contact in AIDS-endemic areas is likely to be associated with early infection and with an increased risk of AIDS among men with HIV infection of unknown duration. Thus, although our analysis had limited statistical power, we conclude that most lifestyle variables appear to act as exposure factors in HIV infection but not as cofactors in the development of AIDS.     

Ocular complications of the acquired immunodeficiency syndrome

The acquired immunodeficiency syndrome (AIDS) affects the ocular structures in several ways. Kaposi's sarcoma has been observed on the bulbar conjunctiva of the globe. Retinal complications, however, are of major concern. Cotton-wool spots are commonly seen in AIDS patients and are usually of no consequence, except that they must be distinguished from the early stages of cytomegalovirus (CMV) retinitis, seen in 20-40% of these patients. CMV causes a necrotic-type retinitis potentially leading to blindness. 9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (DHPG) has been found effective in the short-term treatment of this disorder. It is planned to use AS101 in the regimen to see if a long-term cure from this disease can be affected. Care must be taken in handling ocular tissue of AIDS patients or the re-use of ophthalmic instruments touching the eye of AIDS patients since the human immunodeficiency virus has been found in these structures.     

Disruption of excitatory amino acid transporters in brains of SIV-infected rhesus macaques is associated with microglia activation

Glutamate-mediated neurodysfunction in human immunodeficiency virus (HIV) infection has been primarily suggested by in vitro studies. The regulation of glutamatergic neurotransmission in inflammation is a complex interaction between activation of immune mediators and adaptive changes in the functional elements of the glutamatergic synapse. We have used simian immunodeficiency virus (SIV)-infected macaques to answer the questions (i) whether perturbation of glutamate neurotransmission is evident during progression of immunodeficiency disease and (ii) what are the mechanisms underlying this impairment. Disease progression in SIV-infected macaques both in the periphery and in the brain was documented by clinical and general pathological examination, plasma and brain viral RNA load, T-cell analysis and brain histopathology. We report for the first time, disruption of excitatory amino acid transporters (EAATs), the cardinal glutamate clearing system, during SIV infection and a dramatic loss of EAATs associated with development of rapid acquired immunodeficiency syndrome (AIDS). EAATs impairment was correlated with activation status of microglia. Our data support the glutamate hypothesis for the development of HIV dementia and suggest that the pathogenetic mechanism for the neurodysfunction is the impairment of glutamate clearing which occurs in the stage of AIDS and which is associated with activated microglia.     

NKG2C+ NK cells are enriched in AIDS patients with advanced-stage Kaposi's sarcoma

Kaposi's sarcoma (KS) is an AIDS-defining condition in individuals with human immunodeficiency virus type 1 infection. We investigated the phenotype and function of the NKG2C+ NK cell population in individuals with AIDS and Kaposi's sarcoma. The staging of AIDS KS patients according to the AIDS Clinical Trial Group criteria revealed that patients with the S1 disease stage have a significantly higher proportion of NKG2C+ cells than those with the S0 disease stage. NKG2C+ cells from S1-stage patients are highly enriched for the expression of KIR3DL1, are depleted of NKp46, and respond poorly to major histocompatibility complex class I-positive target cells. These data demonstrate a link between NK cell phenotype and function and disease prognosis in AIDS.     

HIV persistence in monocytes leads to pathogenesis and AIDS

An hypothesis of the pathogenic mechanism leading to acquired immunodeficiency syndrome (AIDS) that places special emphasis on the potential for infected monocytes to act as the reservoir of a persistent human immunodeficiency virus (HIV) infection has been developed. Monocytes may mediate directly the infection and ultimate destruction of helper T cells; this establishes a direct relationship between antigen presentation and HIV dissemination, thus accounting for the cytopathogenic effects and immune system debilitation associated commonly with AIDS. The possibility that this mode of virus dissemination can account for the depletion of helper-T-cell subsets based on their antigen specificity is considered and may explain why the cellular immune response to the virus is ineffective. This concept and may also elucidate the role of intercurrent infections in the development of disease and it suggests mechanistic explanations for the conversion from prodromal to fulminant AIDS.     

Classic AIDS in a sooty mangabey after an 18-year natural infection

Prevailing theory holds that simian immunodeficiency virus (SIV) infections are nonpathogenic in their natural simian hosts and that lifelong infections persist without disease. Numerous studies have reported that SIV-infected sooty mangabeys (SMs; Cercocebus atys) remain disease free for up to 24 years despite relatively high levels of viral replication. Here, we report that classic AIDS developed after an 18-year incubation in an SM (E041) with a natural SIVsm infection. Unlike that described in previous reports of SIV-related disease in SMs, the SIVsm infecting E041 was not first passaged through macaques; moreover, SM E041 was simian T-cell leukemia virus antibody negative. SM E041 was euthanized in 2002 after being diagnosed with severe disseminated B-cell lymphoma. The plasma virus load had been approximately the same for 16 years when a 100-fold increase in virus load occurred in years 17 and 18. Additional findings associated with AIDS were CD4(+)-cell decline, loss of p27 core antibody, and loss of control of SIVsm replication with disseminated giant cell disease. These findings suggest that the time to development of AIDS exceeds the average lifetime of SMs in the wild and that the principal adaptation of SIV to its natural African hosts does not include complete resistance to disease. Instead, AIDS may develop slowly, even in the presence of high virus loads. However, a long-term relatively high virus load, such as that in SM E041, is consistent with AIDS development in less than 18 years in humans and macaques. Therefore, the results also suggest that SMs have a special mechanism for resisting AIDS development.     

Genetic determinants of pediatric HIV-1 infection: vertical transmission and disease progression among children.

It is very likely that perinatal human immunodeficiency virus type 1 (HIV-1) infection is influenced by a combination of virologic and host factors. A greater understanding of the role played by various risk factors for HIV-1 infection is crucial for the design of new preventive and therapeutic strategies. In recent years, a number of studies have suggested that host genetic factors are important determinants of both the susceptibility to perinatal HIV-1 infection and the subsequent pathogenesis of acquired immunodeficiency syndrome (AIDS). Control of HIV-1 infection involves the processing of specific viral peptides and their presentation to cells of the immune system by highly polymorphic human leukocyte antigen (HLA) alleles. The contribution of multiple HLA class I and II alleles in modulating pediatric HIV/AIDS outcomes has now been confirmed by several independent groups. Penetration of HIV-1 into cells is mediated by interaction between CD4 and chemokine receptors that serve as entry coreceptors. Genetic polymorphisms in chemokine ligand and chemokine receptor genes have recently been associated both with mother-to-child HIV-1 transmission and disease progression in children. These observations suggest a key role for genetic factors in pediatric HIV-1 infection. This article describes the current state of knowledge regarding host genetic influences on pediatric HIV-1 infection and discusses the role of these genes in HIV/AIDS pathogenesis.     

The value of primate models for studying human immunodeficiency virus pathogenesis

Abstract: Research on human immunodeficiency virus (HIV) infection is compromised by the obvious limitation in having for study only virus-infected individuals or those exposed to the virus. Steps involved in transmission or pathogenesis require planned experimentation. The identification of animal models of acquired immunodeficiency syndrome (AIDS) has therefore been helpful for evaluating phases of HIV pathogenesis. Of the seven subgenera of lentiviruses now recognized, two share the characteristics with HIV of a T cell tropism and the associated loss of CD4+ cells in the host associated with disease: the feline immunodeficiency virus (FIV) and the simian immunodeficiency virus (SIV) (Table 1). The other animal lentiviruses grow best in macrophages and their infection generally reflects clinical sequellae of infection of this cell type. This review addresses those features of SIV, HIV, and SHIV infections of non-human primates that illustrate the importance of the animal models of AIDS.     

Recent trends in cesarean section rates in Ontario

To assess the economic impact of HIV (human immunodeficiency virus) antibody screening among potential immigrants on Canada''s health care system we estimated the costs and benefits of such screening among the 160 135 immigrants who entered Canada in 1988 using the in-hospital costs of treating AIDS (acquired immune deficiency syndrome) over the 10 years after immigration. This economic model was based on current international HIV seroprevalence data, Canadian immigration statistics and estimates of disease progression. Between 343 and 862 of the immigrants were estimated to have been HIV seropositive; with the use of the enzyme-linked immunosorbent assay and the Western blot technique 310 to 780 of them would have been correctly identified as being seropositive, and 33 to 82 would have been incorrectly classified as being seronegative. Another 16 would have been falsely classified as being seropositive. There would have been 151 to 379 cases of AIDS from 1988 to 1998 among the immigrants identified as being HIV-positive. The estimated total cost of screening would have been $3.3 to $3.4 million. The in-hospital costs of treating HIV-infected immigrants in whom AIDS developed between 1989 and 1998 would have been $5.0 to $17.1 million. Accordingly, screening would have saved $1.7 to $13.7 million over the 10 years after immigration. However, we do not advocate screening on the basis of economic analysis alone and acknowledge that any policy regarding such screening must also incorporate social, legal and ethical considerations.     

Prevention of disease induced by a partially heterologous AIDS virus in rhesus monkeys by using an adjuvanted multicomponent protein vaccine

Recombinant protein subunit AIDS vaccines have been based predominantly on the virus envelope protein. Such vaccines elicit neutralizing antibody responses that can provide type-specific sterilizing immunity, but in most cases do not confer protection against divergent viruses. In this report we demonstrate that a multiantigen subunit protein vaccine was able to prevent the development of disease induced in rhesus monkeys by a partially heterologous AIDS virus. The vaccine was composed of recombinant human immunodeficiency virus type 1 (HIV-1) gp120, NefTat fusion protein, and simian immunodeficiency virus (SIV) Nef formulated in the clinically tested adjuvant AS02A. Upon challenge of genetically unselected rhesus monkeys with the highly pathogenic and partially heterologous SIV/HIV strain SHIV(89.6p) the vaccine was able to reduce virus load and protect the animals from a decline in CD4-positive cells. Furthermore, vaccination prevented the development of AIDS for more than 2.5 years. The combination of the regulatory proteins Nef and Tat together with the structural protein gp120 was required for vaccine efficacy.     

Atopic manifestations in the acquired immune deficiency syndrome: response to recombinant interferon gamma.

Six patients with the acquired immune deficiency syndrome (AIDS) had exacerbations or recurrences of previously quiescent atopic disease when they developed immunodeficiency. Four developed a different atopic illness from that suffered previously. Atopic symptoms developed within three months after the patients developed AIDS or during prodromal illness. Two of the patients were treated with recombinant interferon gamma: both showed a striking improvement in symptoms and cellular immunity. These results indicate that cellular immunity, through interferon gamma, may have a role in regulating atopic disease.