The role of infant immune responses and genetic factors in preventing HIV-1 acquisition and disease progression.

Abstract

Mother-to-child HIV-1 transmission accounts for more than 700 000 new paediatric HIV-1 infections in developing countries each year [1]. This comprises less than one-third of the infants born to human immunodeficiency virus type 1 (HIV-1) infected mothers, the majority of whom remain uninfected despite recurrent risk for contact with the virus in utero, during delivery and through breastfeeding. A comprehensive approach to studying infant immunity against HIV-1 may provide insight into the determinants of HIV-1 acquisition, promote an understanding of resistance to infection in the setting of repeated exposure to the virus and contribute to the development of therapeutic interventions or vaccines against HIV-1 transmission. Several unique features of mother-to-child HIV-1 transmission provide advantages in determining correlates of HIV-1 acquisition and viral immunity when compared to sexual HIV-1 transmission models. Both HIV-1 infected mothers and their exposed infants can be evaluated for viral and immunological factors associated with transmission. HIV-1 exposure can be characterized by quantifying maternal HIV-1 viral load in plasma, breast milk and genital tract secretions, and infant immune responses can be defined simultaneously or near the time of exposure. Timing of transmission can be estimated using HIV-1 polymerase chain reaction (PCR) at birth and at regular intervals after exposure during delivery and breastfeeding. Vertical HIV-1 transmission risk is also higher than sexual transmission risk. Per sexual act, it is estimated that the risk of heterosexual transmission is approximately 0·1% in an antiretroviral naive population [2]. The risk of HIV-1 acquisition during delivery ranges from 10 to 20%, more than 100-fold higher than heterosexual transmission rates. Disparities between heterosexual and vertical HIV-1 transmission rates persist in the setting of antiretroviral therapy. This enables mother–child transmission studies to provide robust epidemiological data regarding specific immune mechanisms and combinations of immune responses that may constitute protective immunity against HIV-1. This review examines the spectrum of innate, humoral and cellular immune responses and genetic factors that have been studied in infants who are HIV-1 infected or HIV-1 exposed and uninfected (Fig. 1). Fig. 1 Immune responses and genetic factors associated with mother-to-child HIV-1 transmission and paediatric HIV-1 disease progression. *May be maternally acquired in utero or via breast milk. †Alloimmunity is dependent on degree of maternal–infant ... INNATE IMMUNITY Innate immune responses are generated rapidly and are important in preventing and containing infections with a variety of viral pathogens. Broad innate immunity may also be capable of protecting against immune-escape viruses generated by more narrow adaptive immune responses. In HIV-1 transmission and disease progression, relevant innate mechanisms of immunity include the activity of natural killer (NK) cells and antiviral proteins such as the CC chemokines, CD8+ antiviral factor (CAF) and secretory leucocyte protease inhibitor (SLPI). Natural killer (NK) cell activity Natural killer (NK) cells induce inflammation and lyse infected cells without prior sensitization and in a non-HLA restricted manner. NK cells from HIV-1 infected individuals release the CC chemokines MIP-1α, MIP-1β and RANTES, three factors that have been shown to inhibit HIV-1 independently in vitro by blocking the CCR5 HIV-1 coreceptor [3,4]. NK cells also act by lysing HIV-1 infected cells via antibody-dependent cellular cytotoxicity (ADCC). This is initiated by binding of NK cell Fc receptors (CD16) to target cells coated with HIV-specific antibodies of the subclass IgG1 [5–7]. HIV-specific ADCC antibodies are directed against the viral envelope glycoproteins gp120 and gp41 and are distinct from virus-neutralizing antibodies [8]. There is conflicting evidence regarding the role of NK cells in containing HIV-1 in chronically infected children and in preventing vertical HIV-1 transmission. Several studies have evaluated HIV-specific ADCC antibody titres in sera of infants born to HIV-1 infected mothers and found that these antibodies are transferred efficiently across the placenta from mother to fetus [9,10]. However, there was no significant correlation between antibody titres at birth and either HIV-1 disease progression during 2 years of follow-up or mother-to-child HIV-1 transmission [9,10]. Active production of HIV-specific ADCC antibodies was observed in the majority of HIV-infected infants only after 12 months of age [10] and effector cells from HIV-1 infected children appear unable to generate NK cell-mediated cytotoxicity [11]. Thus, an immature immune system may account for the absence of ADCC-mediated NK protection against HIV-1 infection in neonates and young infants, despite adequate levels of passively transferred ADCC antibodies. This may contribute to rapid HIV-1 progression in children infected with HIV-1 early in life [10,11].