Increased levels of soluble co-stimulatory molecule PD-L1 (B7-H1) in the plasma of viraemic HIV-1+ individuals.

Recent evidence has revealed that PD-L1 is expressed in two functional forms, namely, a membrane-bound form (mPD-L1) and a soluble form (sPD-L1). The identification of the soluble form of PD-L1 represents the discovery of a new potential mechanism for the activation of the PD-1 pathway that may mediate a physiological apoptotic mechanism through a cell-cell signalling-independent pathway and may also favour T cell dysfunction during HIV infection. Since the presence of sPD-L1 has not been well established in the scenario of chronic viral infection, we investigated the presence of sPD-L1 in the plasma of viraemic HIV+ individuals and the potential mechanism that promotes its production. We report the following: 1) the level of the soluble form of PD-L1 is increased in the plasma of viraemic HIV+ individuals, 2) the level of the soluble form of PD-L1 in viraemic HIV+ individuals correlates with markers of microbial product translocation and inflammation, 3) the expression of the membrane-bound form of PD-L1 on conventional dendritic cells from viraemic HIV+ individuals correlates with the levels of soluble PD-L1 and MMP-2, and 4) monocyte-derived dendritic cells not only increase their expression of mPD-L1 and MMP-2 but also produce sPD-L1 after LPS and TNF-α stimulation, as demonstrated by functional in vitro experiments, which provides insight into the potential source of sPD-L1 production.

Intralesional cidofovir in severe juvenile respiratory papillomatosis.

UNLABELLED: Recurrent respiratory papillomatosis causes significant morbidity among affected children and usually requires frequent surgeries. We present a prospective case series including nine children at a Mexican tertiary referral center. All enrolled patients had severe disease that had required at least four surgical procedures, with a median of 6. Two children had tracheobronchial involvement, one had lung parenchymal disease, and one had a tracheostomy performed during his first surgery. OBJECTIVE: To assess the efficacy of intralesional cidofovir in lowering the surgery rate. STUDY DESIGN: Prospective case series. SETTING: Tertiary referral center in Mexico City. METHODS: Nine Mexican children with severe disease were enrolled. Intralesional cidofovir was applied after surgical debulking at a concentration of 5 mg/mL with a four to six week interval. RESULTS: Six of the nine patients had a notable decrease in the rate of surgeries, with three patients remaining disease-free with follow up ranging from 1.8 to 3.3 years. No patient demonstrated laboratory abnormalities. Two patients showed moderate and mild dysplasia on papilloma biopsy distinguished by a lack of epithelial maturation with no mitoses or cellular atypia. Two patients died several months after the last injection. CONCLUSIONS: Intralesional cidofovir appears to be effective in the treatment of recurrent respiratory papillomatosis, although further studies are required to determine its safety.

Resistencia a los antirretrovirales: Informe preliminar del capítulo de Guatemala, del estudio de epidemiología molecular del VIH en la región de mesoamerica / Antiretroviral resistance: initial report of Guatemala chapter, the study of molecular epidemiology of HIV in the region of Mesoamerica

El uso más extendido de los fármacos antirretrovirales ha traído como consecuencia la transmisión de variantes virales con mutaciones de resistencia que se pueden mantener en individuos sin tratamiento antirretroviral. La frecuencia de estas mutaciones de resistencia transmitida es relativamente alta en países desarrollados, muchas veces con tendencias de aumento. En países en vías de desarrollo, en los que la terapia antirretroviral (ARV) se introdujo posteriormente, las frecuencias de resistencia primaria tienden a ser menores, probablemente porque su uso se encuentra basado en una disponibilidad relativamente limitada...

Resistencia primaria del VIH a los antirretrovirales: informe preliminar del capítulo de Guatemala del estudio de epidemiología molecular del VIH en la región Mesoamericana / Primary HIV resistance to antiretroviral drugs: preliminary report of Guatemala chapter of molecular epidemiology study of HIV in Mesoamerica

Métodos: se seleccionaron pacientes adultos con diagnóstico reciente de infección por VIH, o con diagnóstico previo y que no habían iniciado terapia antirretroviral, que fueron enrolados como parte del estudio Epidemiología Molecular y vigilancia de farmacorresistencia del VIH-1 en la Región Mesoamericana, durante los meses de octubre de 2010 y agosto de 2011 en el Hospital Roosevelt, ciudad de Guatemala. La participación fue debidamente informada y voluntaria...

Risk factors for immune reconstitution inflammatory syndrome under combination antiretroviral therapy can be aetiology-specific.

In order to discriminate general from aetiology-specific risk factors for immune reconstitution inflammatory syndrome (IRIS), we followed up, during six months, 99 patients with advanced HIV infection commencing antiretroviral therapy (ART) without active opportunistic infections or evident inflammation. IRIS predictors were determined by univariate analysis using clinical data from 76 ART-responding patients either completing follow-up or developing IRIS, and by multivariate analysis of inflammation, disease progression and nutrition status variables. We identified 23 primary IRIS events (30.3%). Univariate predictors for all IRIS events were higher platelet counts and lower CD4/CD8 ratio, whereas subclinical inflammation was the multivariate predictor. Platelets, alkaline phosphatase levels and %CD8 T-cells in univariate analysis also predicted mycobacteria-associated IRIS independently, remaining elevated during follow-up. Herpesvirus IRIS was predicted by platelets and inflammation. Indicators of advanced HIV disease and subclinical inflammation jointly predict IRIS, and some are specific of the underlying microbial aetiology, possibly explaining previous reports.

Cornering HIV: taking advantage of interactions between selective pressures.

Adaptive immune responses, cellular restrictive factors and antiretroviral drugs, target multiple regions in the Human Immunodeficiency Virus (HIV) proteome, imposing diverse pressures to viral adaptation. However, the virus is remarkably able to escape from these pressures as mutations are selected. In many cases these mutants have diminished viral fitness. We propose that the concerted action of strategically placed agents and pressures in a host can limit HIV variation capacity while inhibiting its replication. These mechanisms would corner HIV by selecting conflicting adaptive mutations, each having a disadvantage in face of another selective pressure. This would keep the virus unable to efficiently escape the suppressive effects of selective pressures. Cornering between antiretroviral drugs and cytotoxic T lymphocytes may explain recent observations, and can be predicted and used in viral control strategies. This idea can be extended to numerous other identified sites in the viral genome that confer selective pressures. We describe these other sites and how they could be induced to interact in prophylactic or therapeutic cornering strategies, as well as their experimental verifications. Cornering would control HIV infection better than current strategies, focused on few, albeit important, sites in the HIV genome.

[Genetic determinant factors of resistance to HIV infection and of control of progression to AIDS: implications on pathogenesis and therapeutic approaches for the eradication of HIV. A review]. / Los factores genéticos determinantes de la resistencia a la infección por VIH y del control de la progresión al SIDA: implicaciones sobre la patogénesis y las estrategias terapéuticas para la erradicación del VIH. Una revisión.

In this review, we describe and discuss the genetic factors that, up to some point, determine resistance to the infection and control the progression of the disease in HIV-infected individuals. Genetic factors may account for non-progression or slow progression of the disease in some of so called long-term non progressors HIV-infected individuals. In general, this group shows no symptoms for more than 10 years, while their circulating T CD4+ cells levels remain stable and they usually have a low virus load. Even though non-progression and rapid progression phenomenon are still not fully understood, there probability exists that some class I and class II MHC alleles are associated with a greater or smaller risk to develop AIDS. Class I HLA-B*35 and Cw*04 alleles are the ones commonly associated with the rapid transition of the infection into AIDS. In contrast, heterozygosity for class I HLA alleles and, particularly, the absence of HLA-B*35 and Cw*04 may contribute to non-progression. Studies which set forward other HLA alleles as possibly taking part of the pathogenic mechanism of non-progression are also described; although, relevant methodological problems can be noticed. Furthermore, this review explains and discusses allelic variations for some of the components of the chemokine receptors family, particularly the genes which codify for CCR5 and CCR2 and other genetic factors such as the SDF1-3'. A variant of the alpha SDF1 chemokine gene that have been associated with AIDS' slow progression or non-progression in HIV-infected individuals. As a whole, the factors described in this review are those that influence the natural history of the disease due to HIV and give an example of what genetic or multigenetic influence can have over the pattern of evolution of HIV infection. Finally, we mention the possible implications that the identification of the genetic markers has in the pathogenesis of HIV disease and in the development of the new therapeutic strategies to control or eliminate HIV.

Thalidomide as therapy for human immunodeficiency virus-related oral ulcers: a double-blind placebo-controlled clinical trial.

A double-blind, randomized, placebo-controlled clinical trial was performed in Mexico City to evaluate the efficacy of thalidomide in treating oral recurrent aphthae in human immunodeficiency virus (HIV)-infected subjects. Sixteen HIV-infected patients with clinical and histological diagnosis of oral recurrent aphthous ulcerations received randomly an 8-week course of either thalidomide or placebo, with an initial oral dosage of 400 mg/d for 1 week, followed by 200 mg/d for 7 weeks. Ten subjects received thalidomide and six received placebo. At 8 weeks, nine subjects (90%) in the thalidomide group had complete healing of their ulcers, compared with two (33.3%) of the six patients in the placebo group (P = .03). There was a significant reduction in largest ulcer diameter in the thalidomide group. Rash was observed in 80% of the thalidomide patients. Although thalidomide demonstrated an unquestionable benefit in treatment of oral ulcers in HIV patients, caution must be taken given the frequent occurrence of side effects.

[Care for the patient with AIDS]. / La atención del paciente con SIDA.

New concepts regarding the medical care of AIDS patients are described in this paper. Currently, new pharmacologic agents and their combinations with zidovudine are being evaluated in clinical trials to determine their efficacy in the treatment of HIV-infected patients. Nevertheless, zidovudine is still the mainstay of therapy in AIDS patients. Significant findings regarding monotherapy, combination therapy, and immunotherapy for the treatment of HIV infection are also discussed. There is considerable controversy on the optimal time to initiate therapy with antiretroviral agents. The clinician's decision to initiate antiretroviral therapy should consider the expectations of patients in the context of relative benefits and potential toxicities of therapy. The clinician must be aware that rigid universal therapy guidelines for all patients may not be appropriate. Currently available drugs are only palliative and the development of innovative therapeutic strategies for early intervention is indispensable on the basis of recent knowledge of the extremely complex pathogenesis of HIV infection. At present time, the medical care of AIDS patients should be individualized and done in the context of the patient-physician relationship for therapeutic and nontherapeutic decisions.

Cyclospora cayetanensis infection in patients with and without AIDS: biliary disease as another clinical manifestation.

We describe patients with and without AIDS who had Cyclospora cayetanensis infection; these patients were seen at a tertiary care teaching hospital in Mexico City because of diarrheal disease. C. cayetanensis was detected by examination of fresh fecal preparations and acid-fast staining of fecal smears; the presence of other bacteria and parasites was excluded by standard methods. Fecal specimens from 12 patients contained C. cayetanensis. The overall mean duration of illness was 94 days. Seven of the 12 patients had AIDS; these patients presented with more weight loss than did patients without AIDS (P = .04). The patients with AIDS also tended to have a more prolonged illness. Two patients with AIDS had biliary disease that resolved when they received therapy with trimethoprim-sulfamethoxazole for cyclospora infection; the excretion of oocysts also ceased. Our data confirm that C. cayetanensis causes diarrhea in humans and a significant weight loss in patients with AIDS. In addition, Cyclospora could be involved in biliary disease in patients with AIDS.

[Pathogenesis of human immunodeficiency virus infection]. / Patogénesis de la infección por el virus de la inmunodeficiencia humana.

The immunopathogenic mechanisms of the human immunodeficiency virus infection and the precise events that are involved in the clinical latency period are extremely complex and remain unknown. Thus, at the present time, there is no way to prevent or revert the disease, though several and innovative forms of treatment have been developed and different clinical trials on immunization have been conducted. In this review, we describe the molecular biology of HIV-1, the dynamic interactions between HIV and the host, particularly in the clinical latency period, and the factors that induce viral expression. The consequences of HIV infection are influenced by the immunological state of the host, especially by the subtype 1 of CD4+ T cells. The subsequent reaction of the host immune system, with neutralizing antibodies and strong CD8+ T cells response, contain temporarily the course of HIV infection. However, the HIV generates strategies in order to face, evade, and destroy direct or indirectly the immune system. The virus is then activated and replicates without control, producing the progression to AIDS, and inevitably leading to the death. Only the understanding of the pathogenic mechanisms could offer definitive alternative treatment or control of HIV infection.

[T CD4+ cell counts and their use in the management of patients with HIV-1]. / Conteo de células T CD4+ y su uso en el manejo de pacientes con HIV-1.

The hallmark of the HIV-1 infection is the progressive depletion of the circulating CD4+ T cells. The prophylactic, therapeutic and prognosis criteria of the HIV-1 infected patients are based on the measurement of these cells. However, there are serious analytical and biological variations in the count of CD4+T cells. The factors that influence the measurement of the circulating levels of CD4+T cells and its consequences in the clinical management of the HIV-1 infected patients are described in this update. In addition, some recommendations are suggested to reduce these variations.