Disease progression and evolution of the HIV-1 env gene in 24 infected infants☆
Introduction
The broad intrapatient genetic diversity characteristic of the human immunodeficiency virus type 1 (HIV-1) infection is usually assumed to be the result of positive selection, especially at the env gene ( Ross and Rodrigo, 2002, Seibert et al., 1995, Williamson, 2003, Yamaguchi-Kabata and Gojobori, 2000). Early HIV-1 studies suggested that progression to AIDS results from virus adaptation to the host environment (Nowak et al., 1991, Nowak et al., 1996, Wolinsky et al., 1996). Since then, some studies have found a positive relationship between levels of genetic (antigenic) diversity and the rate of disease progression (Strunnikova et al., 1995, Strunnikova et al., 1998), whereas others have found the opposite pattern (Ganeshan et al., 1997, Wolinsky et al., 1996). These apparently contradictory results likely arose because many of these analyses failed to distinguish between adaptive and selectively neutral changes, which is key to understand the interaction between the virus and its host (Williamson, 2003). When this distinction is taken into account, and more patients are compared, it seems clear that positive selection is more prevalent in patients with slow progression rates to AIDS, because their viral population shows higher adaptation rates due to a stronger immune response (Ross and Rodrigo, 2002; although see Viscidi, 1999, Williamson, 2003, Zanotto et al., 1999). Moreover, it has been suggested that an evolutionary slowdown occurs in late infection, caused by the collapse of the immune system, rather than by a reduction in the viral replication rate due to cellular exhaustion (Lemey et al., 2007, Williamson et al., 2005). To further complicate this picture, some studies have shown the occurrence of convergent evolution and the persistence of selection acting at the same sites over long periods of time in patients with slow (Ross and Rodrigo, 2002) and fast progression rates (Strunnikova et al., 1995), while others have failed to observe these patterns (Williamson, 2003), perhaps reflecting the influence of anti-retroviral therapy (Ganeshan et al., 1997, Potter et al., 2006), random genetic drift (Shriner et al., 2004) and recombination (Anisimova et al., 2003) on the distribution of positive selected variants. Moreover, a high portion of the variation at the V3 region of the env gene seems to be neutral (Nielsen and Yang, 1998). Finally, it has been shown that selection in the HIV-1 env gene, though intense, can be context-dependent (Templeton et al., 2004).
Studying the evolutionary relationship of HIV-1 and its host and characterizing the distinct adaptation patterns in different parts of the HIV-1 genome that interact with the immune system will be key to elucidate how HIV-1 overwhelms the immune system and leads to AIDS (Williamson et al., 2005). In this study, we examine in detail the evolution of HIV-1 in 24 infants classified on the basis of progression to AIDS. For that purpose, we have sequenced the C2V3C3 region of the HIV-1 env gene in longitudinal samples (three to seven per patient) obtained from each infant during a period of 3 years. The C2V3C3 region of the env gene is very suitable to study viral adaptation because it is key for entrance of HIV-1 into host cells and is a target of the immune response to HIV-1. The main objective of this study was therefore to decipher the temporal relationship between disease progression and diversity, divergence, selection, and recombination in the HIV-1 envelope gene. Uniquely, because we have sampled infants, we were able to study nearly the entire disease progression cycle – from infection to AIDS – whereas most studies on adults can only begin sampling long after infection and often only shortly before AIDS.
Section snippets
Study population
The study participants were a subset of infants with HIV-1 perinatal infection enrolled in The New York City Perinatal HIV Transmission Collaborative Study, which is an observational cohort study of HIV infected infants born at seven New York City health care institutions since 1986. The enrollment criteria and study protocol design are described in detail elsewhere (Abrams et al., 1995, Thomas et al., 1994). Infants had a medical history, physical examination and phlebotomy done at birth and
Results
The GTR + I + G model was selected as the best-fit model of nucleotide substitution for the combined data set (all patients) (πA = 0.4121, πC = 0.1814, πG = 0.2121, and πT = 0.1943; rCT = 5.3938, rCG = 0.5097, rAT = 0.7055, rAG = 4.0379, and rAC = 1.5957; α = 0.9762 and proportion of invariable sites I = 0.0482). This model is often selected for the HIV-1 env gene (Posada and Crandall, 2001). Upon inspection of the ML tree, we inferred cross-contamination for samples P14.2.3 and P14.2.15, which were eliminated from
Discussion
The study of infected infants provides a comprehensive view of how HIV-1 genetic diversity fluctuates over the entire course of infection leading to AIDS. Most HIV-1 studies are on adults and they only sample at the onset of AIDS, which is well down the timeline from initial infection. Our data have the unique aspect of exploring early infection stages, since the infant's initial samplings were taken close to birth. Similar with other studies (Ganeshan et al., 1997; Shankarappa et al., 1999,
Acknowledgements
This work was supported by NIH grants R01-HD34350 (KAC, RPV) and R01-GM66276 (KAC, DP) and Brigham Young University (EK). DP was supported grant BFU2004-02700 of the Spanish Ministry of Education and Science and by the “Ramon y Cajal” programme of the Spanish government. ACR is currently funded by an Isidro Parga Pondal research fellowship from Xunta de Galicia (Spain). We thank Jing Gu, Samantha Crowe, James Demma and Imran Fatani for generation of sequence data and Emilio Rolán-Alvarez for
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2014, Molecular Phylogenetics and EvolutionCitation Excerpt :Site-specific likelihood differences also show strong variation between spatially proximate sites in support for mono- vs. paraphyly of CC07’s viral lineages (Fig. 3), although we have not quantitatively compared this distribution to expectations under the inferred pattern of recombination. Strong positive selection is known to occur in env, creating the potential for similar selective environments in different host individuals to drive convergence of env sequences in unrelated lineages (Holmes et al., 1992; Strunnikova et al., 1995; Nielsen and Yang, 1998; Ross and Rodrigo, 2002; Edwards et al., 2006; Carvajal-Rodríguez et al., 2008). Similar to recombination, convergence should produce strong variation in preferred topologies across sites.
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2012, Molecular Phylogenetics and EvolutionCitation Excerpt :This exceptional diversity has been examined to infer geographical distribution and dispersion patterns (Lemey et al., 2003; Robbins et al., 2003) and thereby test hypotheses associated with molecular epidemiology (Holmes et al., 1995; Salemi et al., 2008). Phylogenetics has been key to identifying patterns and mechanisms of natural selection (Lemey et al., 2007; Pond et al., 2008; Poon et al., 2010; Templeton et al., 2004), including the intra- and inter-host adaptive forces that shape the evolution of the virus (Carvajal-Rodríguez et al., 2008; Keele et al., 2008a; Salazar-González et al., 2008; Shankarappa et al., 1999), which is essential for effective vaccine development (Frahm et al., 2008). The first applications of phylogenetics to the study of HIV date from the early 1990s and were aimed at inferring the origins of HIV-1 and the classification of HIV into different types (1 and 2), groups (M, N, O within HIV-1), and subtypes (A–D, F–H, and J and K within Group M of HIV-1) (Huet et al., 1990; Fig. 1).