Abstract
During chronic infection, HIV-1 engages in a rapid coevolutionary arms race with the host’s adaptive immune system. While it is clear that HIV exerts strong selection on the adaptive immune system, the characteristics of the somatic evolution that shape the immune response are still unknown. Traditional population genetics methods fail to distinguish chronic immune response from healthy repertoire evolution. Here, we infer the evolutionary modes of B-cell repertoires and identify complex dynamics with a constant production of better B-cell receptor (BCR) mutants that compete, maintaining large clonal diversity and potentially slowing down adaptation. A substantial fraction of mutations that rise to high frequencies in pathogen-engaging CDRs of BCRs are beneficial, in contrast to many such changes in structurally relevant frameworks that are deleterious and circulate by hitchhiking. We identify a pattern where BCRs in patients who experience larger viral expansions undergo stronger selection with a rapid turnover of beneficial mutations due to clonal interference in their CDR3 regions. Using population genetics modeling, we show that the extinction of these beneficial mutations can be attributed to the rise of competing beneficial alleles and clonal interference. The picture is of a dynamic repertoire, where better clones may be outcompeted by new mutants before they fix.
Highlights
HIV-1 evolves and proliferates quickly within the human body [Richman et al, 2003, Moore et al, 2009, Liao et al, 2013], rapidly mutating and often recombining its genetic material among different viral genomes
We show that clonal interference in CDR3 regions reflects a macro-evolutionary drive of the repertoire, either caused by the virus or the overall reorganization of the B-cell receptors (BCRs), even those that do not directly target HIV-1
We compare the structure and dynamics of BCR repertoires sampled over 2.5 years in HIV patients
Summary
HIV-1 evolves and proliferates quickly within the human body [Richman et al, 2003, Moore et al, 2009, Liao et al, 2013], rapidly mutating and often recombining its genetic material among different viral genomes These factors make it very hard for the host immune system to maintain a sustained control of an infection, leading to a long-term chronic condition. Mutated B-cells compete for survival and proliferation signals from helper T-cells, based on the B-cell receptor’s binding to antigens This process of affinity maturation is Darwinian evolution within the host and can increase binding affinities of B-cell receptors (BCRs) up to 10-100 fold [Victora and Nussenzweig, 2012]. The outcome of an affinity maturation process shifts the overall repertoire response against the pathogen [Berek and Milstein, 1987]
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