La historia natural de la infección por el virus de la inmunodeficiencia humana de tipo 1 (VIH-1) es un proceso variable y complejo que, en forma similar a otras infecciones, ha hecho evidente la existencia de mecanismos de resistencia natural que pueden inhibir el establecimiento de la infección o su progresión hacia estadios avanzados. Cuando hay una exposición continua a partículas virales infecciosas, varios mecanismos genéticos e inmunitarios son esenciales para que se establezca la resistencia. El objetivo de este manuscrito fue revisar todos los mecanismos de resistencia al VIH-1, hasta el momento propuestos en seres humanos, y presentar los resultados más importantes que se han obtenido en diferentes estudios realizados en los últimos 10 años de investigación en esta área, en individuos colombianos, particularmente enfocados en determinar los mecanismos involucrados en la protección de un grupo de personas que se han expuesto repetidamente al virus, pero que han permanecido sin evidencia clínica ni serológica de infección por el VIH-1. Aunque los estudios llevados a cabo por nuestro grupo de investigación han corroborado el papel protector de algunos de los mecanismos de protección previamente propuestos, la investigación actual en esta área, a nivel mundial, ha hecho evidente que el fenómeno de resistencia natural depende de múltiples factores con una gran influencia genética, y que sólo mediante estudios multicéntricos que involucren individuos con diferente componente genético, podrán establecerse los mecanismos universales de protección. Profundizar en el conocimiento en esta área permitirá el desarrollo de nuevas medidas preventivas y terapéuticas para la infección por el VIH-1.

The natural history of human immunodeficiency virus type-1 (HIV-1) infection is a complex and variable process that, similarly to other infections, has clearly demonstrated the existence of mechanisms of human natural resistance. The resistance either inhibits the establishment of infection or delays disease progression. When there is continuous exposure to infectious viral particles, several genetic and immunological mechanisms are essential to lead to resistance to HIV-1 infection/progression. The objective of this manuscript was to review the different mechanisms so far proposed to be responsible for HIV-1 resistance and to present the main results derived from 10 years of research in this area among Colombian subjects. In particular, this review focuses on determining the mechanisms involved in the protection of a group of individuals repeatedly exposed to the virus but who remained exempt of serological and clinical evidence of HIV-1 infection. Although the studies carried out in our research group corroborated the protective role of some of the previously proposed mechanisms of protection, ongoing research worldwide has made it clear that the phenomenon of human natural resistance depends on multiple factors with an important genetic influence, and only multicenter studies involving individuals with different genetic backgrounds may determine more universal mechanisms of resistance. Increasing our knowledge in this field will contribute to the development of novel preventive and therapeutic measures.

Given that highly active antiretroviral therapy (HAART) has been demonstrated useful to restore immune competence in type-1 human immunodeficiency virus (HIV-1)-infected subjects, we evaluated the specific antibody response to influenza vaccine in a cohort of HIV-1-infected children on HAART so as to analyze the quality of this immune response in patients under antiretroviral therapy. Sixteen HIV-1-infected children and 10 HIV-1 seronegative controls were immunized with a commercially available trivalent inactivated influenza vaccine containing the strains A/H1N1, A/H3N2, and B. Serum hemagglutinin inhibition (HI) antibody titers were determined for the three viral strains at the time of vaccination and 1 month later. Immunization induced a significantly increased humoral response against the three influenza virus strains in controls, and only against A/H3N2 in HIV-1-infected children. The comparison of post-vaccination HI titers between HIV-1+ patients and HIV-1 negative controls showed significantly higher HI titers against the three strains in controls. In addition, post vaccination protective HI titers (defined as equal to or higher than 1:40) against the strains A/H3N2 and B were observed in a lower proportion of HIV-1+ children than in controls, while a similar proportion of individuals from each group achieved protective HI titers against the A/H1N1 strain. The CD4+ T cell count, CD4/CD8 T cells ratio, and serum viral load were not affected by influenza virus vaccination when pre- vs post-vaccination values were compared. These findings suggest that despite the fact that HAART is efficient in controlling HIV-1 replication and in increasing CD4+ T cell count in HIV-1-infected children, restoration of immune competence and response to cognate antigens remain incomplete, indicating that additional therapeutic strategies are required to achieve a full reconstitution of immune functions.

Hyper-IgE syndrome (HIES) is a rare multisystem disorder characterized by increased susceptibility to infections associated with heterogeneous immunologic and non-immunologic abnormalities. Most patients consistently exhibit defective antigen-induced-T cell activation, that could be partly due to altered costimulation involving accessory molecules; however, the expression of these molecules has never been documented in HIES. Therefore, we investigated the expression of CD11a, CD28, CD40, CD54, CD80, CD86, and CD154 in peripheral blood mononuclear cells from six patients and six healthy controls by flow cytometry after autologous and mixed allogeneic reactions. Only the allogeneic stimuli induced significant proliferative responses and interleukin 2 and interferon gamma production in both groups. Most accessory molecules showed similar expression between patients and controls with the exception of CD54, being expressed at lower levels in HIES patients regardless of the type of stimulus used. Decreased expression of CD54 could partly explain the deficient T cell activation to specific recall antigens in HIES patients, and might be responsible for their higher susceptibility to infections with defined types of microorganisms.