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

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). 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 HLA mismatch. 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) 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]. In addition to mediating HLA-restricted cytolytic activity, CD8+ T lymphocytes can suppress HIV-1 in vitro by secreting a soluble factor or collection of factors. These non-entry inhibitors, known as CD8 antiviral factors (CAF), can block viral replication of both R5 and X4 viruses by inhibiting transcription regulation at the HIV-long-terminal repeat (LTR) [12,13]. CAF appears to be distinct from the CC chemokines but may be related to other known factors, such as the α-defensins-1, − 2 and − 3, and these may contribute in part to its anti-HIV-1 activity [14,15]. The presence of CAF in plasma has been associated with delayed HIV-1 disease progression in several adult cohorts [12,14,16,17]. The role of CAF in protecting against paediatric HIV-1 disease progression and mother-to-child HIV-1 transmission has been investigated ess extensively. Infants are capable of CAF production and this may be stimulated by exposure to HIV-1 in utero and during delivery. In one study, anti-HIV activity attributed to CAF was detected in 16 (52%) of 31 HIV-1 uninfected infants born to HIV-1 seropositive mothers and in none of the 12 control infants born to HIV-1 uninfected mothers [18]. Additional studies will be necessary to define the contribution of CAF to preventing HIV-1 disease progression in children and protecting against HIV-1 transmission in mother–infant cohorts. In both adults and children, CAF holds promise for new therapeutic and immune strategies that mimic its action or promote secretion of CAF factors. Endogenous proteins in saliva, genital secretions and breast milk may provide protection against mother-to-child HIV-1 transmission. Several soluble components of saliva have been demonstrated to have antiviral activity, including lysozyme, cystatins, lactoferrin and secretory leucocyte protease inhibitor (SLPI) [19,20]. Among these, only SLPI inhibits viral replication effectively at physiological concentrations. SLPI is a 12 kilodalton non-glycosylated protein that is secreted by acinar cells of submucosal glands and acts by targeting a host cell protein rather than by interacting with viral proteins (gp120, gp160), transcriptases or proteases [21–24]. One hypothesis is that SLPI stabilizes the host cell membrane after binding to a SLPI binding protein, thus inhibiting HIV fusion and preventing subsequent viral entry into host cells [25]. Three studies have evaluated the protective effect of maternal SLPI in preventing mother-to-child HIV-1 transmission [26–28]. SLPI levels in infant saliva were investigated in a mother–child cohort in Kenya and found to protect against HIV-1 exposure via breastfeeding [26]. In a second study in the Central African Republic, no differences were found when SLPI levels in colostrum and breast milk were compared for transmitting and non-transmitting mothers [27]. A third study, conducted in South Africa, evaluated SLPI levels in vaginal fluid at 28–32 weeks’ gestation and found a significant correlation between higher SLPI levels in vaginal fluids and decreased mother-to-child HIV-1 transmission [28]. The results of these studies are intriguing and suggest that SLPI in vaginal secretions and saliva is an important innate mechanism of defence against HIV-1 infection that may be used effectively for HIV-1 treatment or prevention. HIV-1 replication is suppressed in vitro by the CC chemokines, MIP-1α, MIP-1β and RANTES, and the CXC chemokine SDF-1 [29–31] when these natural ligands bind to CCR5 and CXCR4 cell surface receptors and block or down-regulate coreceptors utilized by HIV-1 [32–35]. While there has been controversy regarding the role of chemokines in vivo, the majority of clinical studies among HIV-1 infected adults suggest that increased MIP-1α, MIP-1β and RANTES protect against progression of HIV-1 to clinical AIDS [36–40]. In paediatric HIV-1 infection, a positive correlation between CC chemokine levels and slow disease progression has also been observed [41]. These studies have encouraged investigators to explore the clinical application of chemokine-based therapies. These include the use of vaccines to increase production of chemokines and the development of antibodies or drugs that block HIV-1 entry or mimic the action of CCR5- and CXCR4-binding chemokines. Vaccines that induce chemokine expression result in down-regulation or blockade of important HIV-1 co-receptors and this may complement HIV-1 specific cellular and humoral protection [42]. Pharmacological or antibody-mediated blockade is another mechanism for down-regulating CCR5 and CXCR4 receptors. In vitro studies have shown that antibodies to these important HIV-1 co-receptors inhibit HIV-1 entry into cells, have a long half-life in vivo, and are able to cross the placenta [43,44]. In addition, inhibition due to chemokines has potential for being effective across subtypes because different HIV-1 strains use the same chemokine receptors to enter cells. This provides distinct advantages over other therapeutic modalities associated with viral mutations and resistance. CC chemokines may also modulate mother-to-child HIV-1 transmission risk. Infants born to HIV-seropositive mothers who remain uninfected during follow-up have significantly higher levels of RANTES production from cord blood PBMCs than infants with perinatal HIV-1 infection [45]. CC chemokines may influence mother-to-child HIV-1 transmission risk by influencing HIV-1 replication in other maternal and infant compartments. Breast milk, cervicovaginal lavage samples, periodontal tissue and human placental tissue have been demonstrated to contain detectable levels of chemokines [46–49]. The humoral arm of the adaptive immune system plays an important role in preventing infection after viral exposures. However, a protective humoral immune response against HIV-1 has been difficult to characterize. It is generally accepted that the generation of high titre antibodies that neutralize HIV-1 is a desirable component of an effective HIV-1 vaccine. However, epitopes required to create an antibody response able to broadly neutralize virus are not characterized easily and HIV-1 mutates rapidly against most HIV-1 specific antibodies [50,51]. In addition to systemic humoral immunity, an effective humoral response at susceptible mucosal surfaces may protect against vertical HIV-1 infection. As infants pass through the birth canal and breastfeed, their oral, nasal, gastrointestinal and conjunctival mucosa are exposed to maternal genital secretions, blood and breast milk contaminated with HIV-1. Immunoglobulins, and in particular secretory IgA, may be critical for protection against viral infection at these sites and may play a similar role in preventing mother-to-child HIV-1 transmission. Maternal IgG with specific activity against HIV-1 is acquired passively by the infant while in utero without selective antibody transfer [52]. Median time to loss of antibody is approximately 10 months and the majority of infants lose maternal IgG by 18 months of life [53]. In large cohort studies maternal HIV-specific IgG has not been associated with protection against mother-to-child HIV-1 transmission [54,55]. In the early 1990s, several studies reported that there was no difference in levels of maternal antibody to the third hypervariable region of gp120, one of the principal HIV-1 neutralization domains, between HIV-1 transmitting and non-transmitting mothers [56–58]. Later studies demonstrated that a high titre antigp160 response and high plasma virus load were independent risk factors for perinatal transmission of HIV-1 [55]. The increased risk of mother-to-child HIV-1 transmission with high anti-HIV antibody titres may be due to confounding, because women with high plasma viral load have high levels of anti-HIV antibodies [54]. Trials using hyperimmune serum containing virus-specific IgG have been conducted to determine whether passively acquired antiviral antibodies modulate virus transmission and disease progression. In the macaque model, simian immunodeficiency virus hyperimmune serum (SIVIG) given subcutaneously prior to oral SIV inoculation has been shown to protect newborns against infection [59], and when administered during early infection SIVIG has been associated with delayed disease progression in infant macaques [60]. These results suggest that passively acquired anti-HIV IgG may decrease perinatal HIV infection and may be an effective intervention. The role of hyperimmune IgG has also been studied in a paediatric clinical trial [61]. The Pediatric AIDS Clinical Trials Group protocol 185 evaluated whether HIVIG infusions administered monthly during pregnancy and to the neonate at birth would significantly perinatal HIV transmission rates when to administered the This study not a protective effect for rates of HIV-1 transmission in the setting of the to whether can perinatal transmission. Additional studies are and may that there is a to using HIVIG in developing countries or less are the of and breastfeeding HIV-1 transmission during the against vertical HIV-1 transmission correlates with viral neutralization activity of HIV-1 specific antibodies Several studies have the of sera to neutralize its virus and virus from other mothers mothers antibodies against virus more than transmitting In addition, mothers with antibodies also at This provides evidence that antibody responses contribute to the risk of mother-to-child HIV-1 transmission. There are several for an HIV-1 exposed fetus or neonate to from including transfer and the of HIV-1 antibodies via at the time of antibody transfer an effective response in the one that be or of HIV-1 infected women in the second and third has not been associated with in HIV binding and neutralization antibodies administered on the other promise for effective of perinatal and breast milk HIV-1 transmission. Both and treatment with a of three human antibodies have been shown to protect macaques from mucosal with a immunodeficiency virus In a subsequent study the same antibody was used significantly the of antibodies necessary and their potential use in more macaques with this were against oral while control infected there have not been human to the or of passively administered human antibodies. antibodies are and may be to but are to play an important role in the of HIV-1 transmission. may be in HIV-1 infected women are not the time of delivery and unable to from interventions to decrease HIV-1 transmission. Infants are exposed to HIV-1 during delivery and through breastfeeding via and gastrointestinal may contribute to preventing HIV-1 infection at these mucosal surfaces by HIV-specific has been found in uninfected adults and has been shown to neutralize different HIV-1 subtypes have demonstrated that an HIV-specific response can be at oral and other mucosal surfaces with vaccines administered either via mucosal or systemic This HIV-specific may be capable of HIV-1 in directed of of HIV-1 specific humoral immune responses at oral or genital mucosa is to have a on development because the majority of HIV-1 transmission across mucosal surfaces In with humoral immune virus-specific cell-mediated immunity is for containing and viral In HIV-1 infection, cellular immune responses contribute to early and of these responses has been a target for vaccines to the of HIV-1 infection and disease progression. immunity against HIV-1 HIV-specific CD8+ T lymphocytes T cells and natural killer (NK) cells. CD8+ and T cell activity play an important role in and HIV-1 infection and it is that these responses contribute significantly to protection against HIV-1 transmission. HIV-1 infection in adults is by a in CD8+ T lymphocytes and control of the of production of antibodies detected less in HIV-infected infants than in children and adults are to be important of early HIV-1 infection 1). responses may also HIV-1 disease progression and in HIV-1 infection, HIV-specific have been shown to with T cell and with HIV-1 viral an that was independent of the degree of These and several other studies that found no between activity and disease progression and from children a of 1). immune responses in HIV-1 infants and of responses and with HIV disease progression not responses were in to repeated on the same immune responses in HIV-1 infants and of responses and with HIV disease progression not responses were in to repeated on the same The role of infant HIV-1 specific responses in preventing vertical HIV-1 transmission is less The fetus is capable of responses against specific such as The evidence in of a protective role for in utero and during early is from HIV-1 specific responses in HIV-1 exposed infants who not infected In these CD8+ T cell responses specific to HIV-1 were found in blood and in cord blood from HIV-1 uninfected of studies detected responses in HIV-1 uninfected infants and of the infants studied positive responses 1). and the use of a variety of with different levels of may account in part for the of positive HIV-1 specific responses observed in different cohorts. immune responses in HIV-1 uninfected infants and children with HIV-1 exposure cord blood responses in to repeated on the same immune responses in HIV-1 uninfected infants and children with HIV-1 exposure cord blood responses in to repeated on the same that responses protect against vertical HIV-1 transmission also from the that HIV-1 exposed infants are more to infected with a viral that has maternal responses in HIV-1 uninfected infants are to determine whether responses protect against of HIV-1 infection or as a for HIV-1 exposure. Additional in this will contribute data from a of mother–infant and may to the clinical of these The majority of vaccines in clinical are to promote HIV-specific cellular immune responses Several of these HIV-1 vaccines have responses in HIV-1 uninfected adults but studies have at the of HIV-1 vaccines in infants or young In one study among HIV-1 infected infants with disease infants with a HIV-1 were significantly more to a response than the of the in a paediatric It is not known whether this will into a protective cellular immune response for HIV-1 uninfected infants with this and similar There is evidence that HIV-specific T cells contribute to control of in adults In HIV-1 infected infants, HIV-specific T responses have been detected and associated with Infants were found in one study to more rapidly to AIDS and in the absence of production of HIV-specific one of the secreted by T cells T cell activity has also been associated with early HIV-1 specific responses in infants with delayed HIV disease progression [41]. HIV-specific T responses have been reported in cord blood and blood from HIV-1 uninfected infants, that HIV-specific T cells contribute to preventing mother-to-child HIV-1 transmission. These infants not HIV-1 despite exposure to maternal virus in genital secretions, blood and breast milk In the of these investigators found that a high of HIV-1 exposed infants T cell responses in cord blood that were associated with significant protection against HIV-1 acquisition during delivery and breastfeeding. These responses are in mother–infant perinatal for of HIV-1 transmission into the immunological of maternal antiretroviral will to between this important and perinatal and breast milk HIV-1 transmission. It is whether infants are capable of T responses similar to demonstrated by adults after with an HIV-1 and have demonstrated a between HIV-specific activity and T cell responses in infants The contribution of HIV-specific T activity to and responses may be necessary to induce an effective response to a and in HIV-1 co-receptors and human leucocyte influence to HIV-1 infection and may determine the of the antiviral immune response of or understanding of these genetic factors may to the development of vaccines and with activity, and thus of the most evidence that chemokines are to mother-to-child HIV-1 transmission and disease progression from of chemokine with protection from HIV-1 The most investigated CCR5 is a natural that results in a protein not on the cell surface who are for this have been reported to be to infection with R5 HIV-1 HIV-1 infected women who are for have decreased transmission to infants compared to HIV-1 infected mothers with CCR5 the region of CCR5 are found in African individuals and in a perinatal study among HIV-1 infected breastfeeding for the was associated with increased among women during follow-up However, there was no with mother-to-child HIV-1 transmission or infant disease progression. less are the SDF-1 and RANTES The SDF-1 SDF-1 is a to A in the region of an that is in African and other In a study in the SDF-1 was in approximately of HIV-1 seropositive study and for the SDF-1 was associated with increased breast milk HIV-1 transmission Among HIV-1 infected children in the SDF-1 was significantly with disease progression In this study, of and of rapid were for SDF-1 none of the were for the The RANTES and have in the In these have been associated with HIV-1 disease progression and with an risk of HIV-1 acquisition, in who the The effect of these on vertical HIV-1 transmission or HIV-1 infection in infants has not been leucocyte can determine HIV-1 epitopes bind and effectively epitopes are by and HLA to CD8+ T cells and T cells Thus, by specific HLA may promote an immune response that against HIV-1 transmission or HIV-1 infection Several and have been associated with an risk of HIV-1 disease progression in several different HLA at has also been associated with more rapid disease progression in adults because a less collection of epitopes to the immune system than In children, more rapid HIV-1 disease progression has been associated with HLA and the with progression associated with HLA between specific and HIV-1 mother-to-child in a review by have been in studies conducted in infants in and and were associated with increased HIV-1 and several were associated with decreased transmission has been conducted on HLA and vertical HIV-1 transmission among breastfeeding from developing In an African breastfeeding cohort and found that a of related HLA subtypes the was associated with significantly decreased risk of infant HIV-1 infection during the months This study not protection against breast milk HIV-1 transmission with thus intriguing the and of exposure correlates of transmission. In addition to the role of investigators have evaluated the role of HLA between mother and in vertical HIV-1 transmission These studies have that there is increased risk of transmission for infants who a of with their HLA may transmission of that have a cellular immune responses by the mother and may also protect infants from HIV-1 infected cells from a mother with a different HLA type but this has not been provide a unique to the contribution of HLA to cellular immunity against HIV-1. The of HLA in a population may also be relevant to the of an effective or therapeutic vaccine. HLA have been associated with responses to HIV-1 vaccines in adults studies in paediatric may increase understanding of the role of HLA in infant immune responses and mother-to-child HIV-1 transmission risk. There are potential correlates of infant immunity that are associated with for mother-to-child HIV-1 transmission and paediatric HIV-1 disease progression, it that a of cellular and innate responses is for of HIV-1 acquisition in infants (Fig. 1). antibodies and several different components of the innate immune system are among the most for a and effective immune have demonstrated that of antibodies capable of HIV-1 in vitro can infection in and these are in human paediatric in this review also a role for cellular immune responses in viral replication and that CD8+ or T cell responses may provide protection against vertical HIV-1 transmission. Several innate immune including CC chemokines and have been associated with transmission risk and new for vaccines and therapeutic studies have demonstrated between innate and acquired immune responses. These are intriguing and suggest that vaccines to induce innate immunity in with adaptive immunity may provide using a mother-to-child transmission may to define these immune responses and among This will to into the different of transmission utero, breast and their contribution to risk of HIV-1 infection and of protective exposure effective immune responses in utero may not into protection against or breast milk transmission. The age of the infant or and the of infection are also important these may determine whether or not a is able to generate an immune A more of this is the large blood from young infants for comprehensive immunological The of vertical HIV-1 transmission are by several factors that this an for determining protective immune These include high HIV-1 transmission rates from the to both mother and infant near the time of and regarding of infection. Thus, when conducted in with in mother-to-child HIV-1 transmission may provide on correlates of of HIV and development of other therapeutic that may both adults and is by the of is an Pediatric AIDS