Neurotropism of Human Immunodeficiency Virus

Three major characteristics of human immunodeficiency virus (HIV) infection define HIV as neurotropic. 1) Clinically, distinct neurological syndromes are associated with HIV infection and 2) presence of the virus as well as 3) pathological changes can be demonstrated in the central nervous system. Spread of HIV to the brain seems to be the general rule. Virus expression appears to be restricted during the asymptomatic period but increases with severity of HIV infection. Whether this reflects the emergence of virus variants with increased replicative capacity in brain cells has yet to be elucidated.     

Estimation and Comparison of Salivary Secretory Leukocyte Protease Inhibitor in Human Immunodeficiency Virus Patients and Healthy Individuals

Aim:

Transmission of human immunodeficiency virus (HIV) in the oral cavity is a rare event, despite detectable virus in saliva and oropharyngeal tissues of infected persons, unlike other mucosal sites. Secretory leukocyte protease inhibitor (SLPI) has been suggested as the main soluble factor responsible for the HIV inhibitory effect of saliva. The study was designed to estimate and compare the salivary SLPI levels in HIV patients and healthy controls. Furthermore, the relationship between salivary SLPI levels and disease severity was also investigated.

Materials and Methods:

Unstimulated whole saliva specimens were collected from 60 HIV-infected and 20 healthy subjects. Disease severity was determined by CD4 count in HIV subjects, who were divided into two groups: ≥200 cells/μL (n = 30) and < 200 cells/μL n = 30. Salivary SLPI levels were determined by enzyme-linked immunosorbent assay.

Results:

Numerically higher SLPI levels were observed in HIV subjects 193.342 ng/mL vs. 190.587 ng/mL; P = 0.517. A nonsignificant negative correlation was noted between CD4 counts and SLPI levels r = −0.037, P = 0.781.

Conclusion:

The salivary anti-HIV factor, SLPI, is not only preserved in HIV infection but its concentration may even get enhanced in the infection. However, the clinical significance of SLPI levels and disease severity should be investigated further with a larger sample of patients.     

Neuropathology of Human Immunodeficiency Virus Infection

Neuropathology has defined novel HIV-specific diseases at tissue level: HIV encephalitis and HIV leukoencephalopathy. Both occur usually in the later stages of the AIDS infection and consistently demonstrate large amounts of HIV products. In contrast to this HIV-specific neuropathology, HIV-associated neuropathology features unspecific syndromes with disputed relation to HIV infection: myelin pallor, vacuolar myelopathy, vacuolar leukoencephalopathy, lymphocytic meningitis, and diffuse poliodystrophy. All types of neuropathology may contribute to clinical manifestation according to severity, extent, and distribution of lesions, but clinico-pathologic correlation may be poor in the individual case. Neuropathologic and other data suggest two major pathogenetic pathways of HIV-associated CNS damage: First, systemic and local increase of the virus load leads to HIV encephalitis or HIV leukoencephalopathy; this is corroborated by prominent HIV production within such lesions. Second, neuronotoxicity by HIV proteins or factors secreted from infected cells is supported by histological changes of diffuse poliodystrophy and by morphometric loss of frontocortical neurons.     

Serum Protease Inhibitors in the Blood Clearance of Subtilisin A

The plasma clearance of a broad spectrum bacterial protease, subtilisin A, as a function of its binding to serum protease inhibitors and antibodies has been studied in rabbits.When administered in trace quantities, 80% of the active radiolabelled enzyme formed complexes with α-macroglobulins and the remainder with α₁-antitrypsin. The formation of complexes with these inhibitors produced a 15-16 fold increase in the rate of elimination of the enzyme from the blood. Enzyme-α-macroglobulin complexes had the fastest elimination rates (half-life approximately 2 minutes), exceeding the speed by which the enzyme was eliminated as antigen-antibody complexes. The clearance of enzyme-α₁-antitrypsin complexes was considerably slower.A dual isotope technique was applied to the post mortem analysis of the quantitative distribution in the principal reticuloendothelial organs and in muscles of intravenously administered enzyme-inhibitor complexes. There were marked differences in this respect between complexes of enzyme formed with α-macroglobulins and with α₁-antitrypsin.     

Immunological Changes in Human Immunodeficiency Virus (HIV)-Infected Individuals During HIV-Specific Protease Inhibitor Treatment

The present study examines the influence of effective anti-retroviral treatment on immune function, evaluated by a broad array of immunological tests. We followed 12 individuals infected with human immunodeficiency virus (HIV) for 6 months after initiation of combination anti-retroviral treatment including a protease inhibitor. Unstimulated and pokeweed mitogen (PWM)-, interleukin (IL)-2- and phytohaemagglutinin (PHA)-stimulated lymphocyte proliferative responses increased during follow-up reaching average levels from 1.3-fold (PHA) to 3.7-fold (PWM) above baseline values. The total CD4+ lymphocyte count increased mainly due to increases in numbers of CD4+ CD28+ and CD4+ CD45RO+ cells, whereas increases in numbers of CD4+ CD45RA+ cells contributed little to the increase in CD4+ cell count. The total cytotoxic T-cell (CTL) killing of autologous B cells infected with HIV-encoding recombinant Vaccinia virus was increased after 3-6 months, whereas the specific HIV-directed CTL activity and the concentration and lytic activity of natural killer (NK) cells were unchanged during follow-up. These results demonstrate that the initiation of a treatment including an HIV protease inhibitor is followed by an increase in lymphocyte proliferation and lymphocyte-mediated cytotoxicity. However, unchanged levels of specific HIV CTL and NK cell activity warn us that not all measures of immune function may respond simultaneously to anti-retroviral treatment.     

Ultrastructural Pathology of Human Immunodeficiency Virus Infection

The electron microscope has been used with great skill in many aspects of the acquired immunodeficiency syndrome. It has played a critical role in classifying the human immunodeficiency virus, in characterizing the morphogenesis and gene products of the virus, and in elucidating the host cell targets and interactions. With the aid of the electron microscope, new opportunistic pathogens are being identified, and particularly difficult diagnoses are being made. Extrapolations from observations made at the ultrastructural level to the light microscopic level have provided criteria for the diagnosis of several infectious agents. As with any powerful scientific tool, observations must be interpreted with great care by scientists experienced in electron microscopy.     

Effect of Human Immunodeficiency Virus Infection on Plasma Bactericidal Activity against Salmonella enterica Serovar Typhimurium

Individuals with human immunodeficiency virus (HIV) infection have increased susceptibility to invasive disease caused by Salmonella enterica serovar Typhimurium. Studies from Africa have suggested that this susceptibility is related in part to the development of a high level of lipopolysaccharide (LPS)-specific IgG that is able to inhibit the killing of S. Typhimurium by bactericidal antibodies in healthy individuals. To explore this issue further, we examined the bactericidal activity against S. Typhimurium using serum and plasma samples from healthy controls and various clinical subgroups of HIV-infected adults in the United States. We found that the bactericidal activity in the samples from HIV-positive elite controllers was comparable to that from healthy individuals, whereas it was significantly reduced in HIV-positive viremic controllers and untreated chronic progressors. As demonstrated previously for healthy controls, the bactericidal activity of the plasma from the elite controllers was inhibited by preincubation with S. Typhimurium LPS, suggesting that it was mediated by anti-LPS antibodies. S. Typhimurium LPS-specific IgG was significantly reduced in all subgroups of HIV-infected individuals. Interestingly, and in contrast to the healthy controls, plasma from all HIV-positive subgroups inhibited in vitro killing of S. Typhimurium by plasma from a healthy individual. Our results, together with the findings from Africa, suggest that multiple mechanisms may be involved in the HIV-induced dysregulation of humoral immunity to S. Typhimurium.     

Resistance-Associated Mutations in the Human Immunodeficiency Virus Type 1 Subtype C Protease Gene from Treated and Untreated Patients in the United Kingdom

This work reports the variability of human immunodeficiency virus type 1 (HIV-1) protease from treated and untreated patients infected with HIV-1 subtype C in the United Kingdom. The most common primary mutation observed in treated patients was L90M. D30N, M46I, V82A/F, and I84V were seen rarely. M36I and I93L mutations were observed in nearly all samples from both treated and untreated patients and so cannot be considered as resistance-associated mutations in this subtype.     

Non-M Variants of Human Immunodeficiency Virus Type 1

SUMMARY

The AIDS pandemic that started in the early 1980s is due to human immunodeficiency virus type 1 (HIV-1) group M (HIV-M), but apart from this major group, many divergent variants have been described (HIV-1 groups N, O, and P and HIV-2). The four HIV-1 groups arose from independent cross-species transmission of the simian immunodeficiency viruses (SIVs) SIVcpz, infecting chimpanzees, and SIVgor, infecting gorillas. This, together with human adaptation, accounts for their genomic, phylogenetic, and virological specificities. Nevertheless, the natural course of non-M HIV infection seems similar to that of HIV-M. The virological monitoring of infected patients is now possible with commercial kits, but their therapeutic management remains complex. All non-M variants were principally described for patients linked to Cameroon, where HIV-O accounts for 1% of all HIV infections; only 15 cases of HIV-N infection and 2 HIV-P infections have been reported. Despite improvements in our knowledge, many fascinating questions remain concerning the origin, genetic evolution, and slow spread of these variants. Other variants may already exist or may arise in the future, calling for close surveillance. This review provides a comprehensive, up-to-date summary of the current knowledge on these pathogens, including the historical background of their discovery; the latest advances in the comprehension of their origin and spread; and clinical, therapeutic, and laboratory aspects that may be useful for the management and the treatment of patients infected with these divergent viruses.     

Initial Therapy for Human Immunodeficiency Virus: Broadening the Options

Abstract

The goal of investigation into new therapeutic options for HIV/AIDS is to further the achievements of highly active antiretroviral therapy by developing new drugs with improved efficacy. Although several therapies are currently available for initial therapy in HIV-infected patients, ongoing research focuses on additions to existing and novel drug classes that might have improved pharmacokinetic and tolerability profiles, as well as on new therapeutic combinations that might result in synergistic activity. To retain activity against resistant strains, novel drugs need to target the numerous critical points in the life cycle of HIV, inhibiting different enzyme subsites than those affected by antiretroviral agents currently in use. An improvement in patient adherence to therapy is another key objective of efforts in HIV treatment, as suboptimal drug levels are a main determinant of antiretroviral regimen failure. This article reviews the current classes of antiretroviral agents in development, describing the clinical data obtained to date. These agents may have potential use as initial therapy in HIV patients.     

Advances and Failures in Preventing Perinatal Human Immunodeficiency Virus Infection

Summary: An estimated 2.5 million children are currently living with HIV, the vast majority as a result of mother-to-child transmission. Prevention of perinatal HIV infection has been immensely successful in developed countries. A comprehensive package of services, including maternal and infant antiretroviral therapy, elective cesarean section, and avoidance of breast-feeding, has resulted in transmission rates of less than 2%. However, in developing countries, access to such services is often not available, as demonstrated by the fact that the vast majority of children with HIV live in Africa. Over the past few years, many developing nations have made great strides in improving access to much-needed services. Notably, in eastern and southern Africa, the regions most affected by HIV, mother-to-child-transmission coverage rates for HIV-positive women increased from 11% in 2004 to 31% in 2006. These successes are deserving of recognition, while not losing sight of the fact that much remains to be done; currently, an estimated 75% of pregnant women worldwide have an unmet need for antiretroviral therapy. Further work is needed to determine the optimal strategy for reducing perinatal transmission among women in resource-poor settings, with a particular need for reduction of transmission via breast-feeding.     

Human Immunodeficiency Virus and Leprosy Coinfection in Pune,India

We report eight cases and the incidence of leprosy in human immunodeficiency virus (HIV)-infected individuals after initiation of antiretroviral treatment (ART). The incidence of leprosy in patients on ART was 5.22 per 1,000 person-years (95% confidence interval, 2.25 to 10.28). This high incidence suggests that there should be regular examination of HIV-infected individuals for clinical signs of leprosy.Although there is a declining trend in the global burden of leprosy, there are 15 countries in Asia and Africa which account for 94% of the global total of the new-case detection rate. India is one of the countries where ≥1,000 new cases of leprosy were reported during 2006 (14). Human immunodeficiency virus (HIV) and leprosy both are feared due to the associated social stigma, and leprosy can manifest as immune reconstitution inflammatory syndrome (IRIS) in HIV-infected individuals (9). The first case of leprosy-associated immune reconstitution disease was reported in 2003 for a Ugandan living in London, United Kingdom (5). Later leprosy was described as a manifestation of IRIS in many instances (8, 10).Antiretroviral treatment (ART) for HIV infection is now available in resource-poor regions where leprosy is still endemic, such as South America, Africa, and Asia, including India. India accounts for half of the world''s leprosy cases due to its population of more than 1 billion, even though a nationwide prevalence of less than 1 case/10,000 population was reported in 2005 (4). In addition, India also has the third largest burden of HIV-infected individuals (12). In spite of having a large burden of both leprosy and HIV, there are very few published reports of HIV-leprosy coinfection from India. We report eight cases of incident leprosy in HIV-infected patients who were on ART and the incidence of leprosy in HIV-infected individuals on ART.This report is from the Amrita Clinic of PRAYAS, a nongovernmental organization working on HIV/AIDS in Pune, in the state of Maharashtra, India. We retrospectively analyzed data on HIV-infected patients who initiated ART between January 2003 and December 2006 and we studied their follow-up till December 2007 to evaluate the incident cases of leprosy. ART was provided following the national guidelines for treatment of HIV infection (7).Diagnosis of leprosy was based on the clinical signs and symptoms and demonstration of acid-fast bacilli in the slit skin smears by Ziehl-Neelsen staining. All patients with leprosy received multidrug treatment per the WHO guidelines (15).Several definitions of IRIS have been utilized, each incorporating the general concept that cases of IRIS need to have an inflammatory component occurring in the setting of immune reconstitution that cannot be explained by drug toxicity or a new opportunistic infection (1, 6). We have considered leprosy manifestation after starting ART with increase in CD4⁺ cell count, inflammatory response as seen by neuritis, type I or type II leprosy reaction, or need for the use of steroids for the control of inflammation as a criterion for defining leprosy manifestation as IRIS. Statistical analysis was done using STATA (version 8.0).Between January 2003 and December 2006, among the 1,002 HIV-infected patients who started ART for HIV infection and were followed up till December 2007, eight incident cases of leprosy were detected. None of them had clinical evidence of leprosy at the time of initiation of ART. Table ​Table11 describes the details of these eight patients. All the patients except for one were males, and the mean age of the patients with leprosy was 33.8 years (standard deviation [SD], 5.1 years; range, 27 to 42 years). Four patients had paucibacillary leprosy, and four patients had multibacillary leprosy. The mean CD4⁺ cell count of incident leprosy cases was 326 (median, 245; SD, 255.5; range, 99 to 892). Of these eight patients, three had other opportunistic infections such as pulmonary tuberculosis, abdominal tuberculosis, and herpes zoster. The mean number of months to develop leprosy after starting ART was 13.8 months (SD, 14.3 months; range, 2 to 43 months). All eight patients completed their leprosy treatment and recovered completely. Although eight patients developed incident leprosy, six of them developed leprosy within 2 years of starting ART and two patients had delayed manifestations, with one patient developing leprosy after 28 months and the other after 43 months. These 1,002 patients on ART contributed to 1,532.5 person-years, and hence, the overall incidence of leprosy after starting ART was 5.22 per 1,000 person-years (95% confidence interval, 2.25 to 10.28).

TABLE 1.

Details of HIV-infected patients on ART with incident leprosy^a