Boundary-Breaking Evolution via B Lymphocyte Clonal Selection in Response to HIV-1

A central focus of recent research aimed at developing a vaccine for HIV-1 is the identification of potent broadly-neutralizing antibodies (bNAbs).  Due to work from several laboratories, many such antibodies have now been identified, produced in quantity as monoclonal antibodies, and characterized with respect to key properties such as epitope specificity, affinity for the corresponding HIV-1 epitope, and neutralizing activity against many strains of varying susceptibility to antibody-mediated inactivation (important examples of these publications are: Scheid et al., 2009; Walker et al., 2009; Wu et al., 2010; Walker et al., 2011; Huang et al., 2012).  These successes notwithstanding, the scale of the challenge facing the vaccine developers is clarified by the following facts: 1) potent bNAbs only develop in 10-30% of infected individuals, 2) it typically takes between two and three or four years after initial infection for these antibodies to appear in the blood of these individuals, and 3) antibodies with the desired attributes often have extraordinary numbers of somatic mutations in the variable domains that mediate binding to the HIV-1 antigen (Klein et al., 2013a).   A study (Klein et al., 2013b) published earlier this year from the laboratory of Michel Nussenzweig both illuminates one possible factor accounting for the impressive length of time and number of mutations associated with the generation of potent bNAbs and provides an extraordinary example of the power of intense selection to confound expectations arising from previously observed associations.  In this instance, the undermined expectations related to the well-established functional correlates of hypervariable and framework regions within antibody variable domains. (more…)

Are Viruses Alive?

 

Recently, a valued friend and scientific colleague of mine (Jonathan Yewdell of the NIAID in Bethesda) made me aware of a netcast (http://www.twiv.tv/) and associated blog (http://www.virology.ws/) relating to virology.  The originator of both is Vincent Racaniello, a well-known and highly regarded virologist and professor of microbiology at Columbia University.  Dr. Racaniello currently happens to be curating a survey (http://www.virology.ws/are-viruses-alive/) asking people to answer the question: “Are viruses living?” (more…)

A Possible Evolutionary Explanation for the Frequency of CCR5Δ32

In 1996, Dean et al. (Science), demonstrated that a loss-of-function allele (CCR5Δ32) encoding a version of the chemokine receptor, CCR5, confers very substantial resistance to infection with HIV-1 in the homozygous state and slows progression in the heterozygous state.  Given the relatively recent origin of HIV-1, this finding raised the question of what source of selection could account for the frequency, approximately 0.08 among Caucasians according to Dean et al., of this allele.  A recent paper (Alonzo et al., 2013) offers new information on a relationship between CCR5 and a different pathogen that might offer insight into the evolutionary trajectory of CCR5Δ32.

The new study presents compelling evidence that leukotoxin ED (LukED), one of a family of bi-component exotoxins produced by Staphylococcus aureus, can bind to CCR5 and thereby cause cell death.  LukED consistently produces substantially more cytotoxicity for CCR5+ than CCR5 cell lines of several types.  Ligands for CCR5, including the drug, maraviroc, which is approved for clinical treatment of HIV-1 infection, significantly inhibit both the binding of LukED to cells and the magnitude of associated cytotoxicity.  LukED also binds to and kills CCR5+ primarycells, such as human memory T cells, macrophages, and dendritic cells. (more…)

Humoral Immune Responses to HIV-1: Fighting Evolution with Evolution

Among the most pressing global public health problems at present is the AIDS epidemic.  While it is clear that chemotherapy and behavioral interventions have much to offer in limiting the spread of infections by the causative virus, HIV-1, interest in developing a vaccine remains strong.  Immunization would potentially provide a relatively cost-effective and scalable approach to minimizing the incidence of new infections on a global scale.

However, HIV-1 presents numerous challenges to would-be vaccine developers.  There are many different lineages of HIV-1 viruses with different clades dominating in different geographic regions of the world.  Even in a single infected patient, HIV-1 continues to generate many variants.  Astonishingly, according to Korber et al. (2001), “The diversity of influenza sequences world-wide in any given year appears to be roughly comparable to the diversity of HIV sequences found within a single infected individual at one time point ….  The virion surface protein, gp120, which is critically involved in infecting host cells and is a major target for protective antibodies, contains regions that are especially variable in amino acid sequence.

In addition to the serious challenge of eliciting an immune response, of whatever sort, that can effectively provide immunity to the many viral variants in circulation, it remains unclear what types of immune responses are essential for providing a high level of protection against infection or disease.  Some investigators are focsed on eliciting strong cell-mediated immune response.  Others are devoting their efforts to generating humoral responses including potent and broadly-neutralizing antibodies.  There are several recent and interesting reports pertaining to this latter effort. (more…)

Evolutionary Origins of a Potent Broadly-Neutralizing Antibody to HIV-1

Two recent papers published online at scienceexpress.org describe studies of antibodies claimed to interfere with infection of host cells by a wide range of HIV-1 strains.  These studies strongly suggest that the evolutionary potential of the humoral immune response may be necessary to combat the diversity of HIV-1 antigens that results from the extraordinary pace of HIV-1 evolution. (more…)