As expected the majority of our putative transmission cluste

As expected the majority of our putative transmission clusters were predominantly males who were MSM, since the majority of participants were from HIV research programs focused on the MSM population of San Diego. However, in transmission clusters comprised predominantly of heterosexuals, there was a predominance of females. This lack of males in putatively inferred transmission clusters has been demonstrated previously (Hue et al., 2014). Although injection drug use could lead to female–female transmission, unidentified infected male contacts of our sampled FSW are likely to be involved in these transmission clusters. Identification of these men will require different recruitment methods than those currently being used and underscores the importance of identifying and testing partners of high-risk individuals. This cross-border molecular epidemiologic study has several limitations, the most important of which is sampling bias. Different methodologies were used to collect data across the different studies ranging from respondent driven sampling (Detection of HIV in Latinos, El Cuete, SD PIRC, and STAHR (Garfein et al., 2012)), passive enrollment (SD PIRC), venue based recruitment (SDPIC, Detection of HIV in Latinos, and STAHR-II (Robertson et al., 2014)), time location sampling (El Cuete and STAHR-II), partner identification (Amigos, SD PIRC), and convenience sampling (Hombre Seguro, Amigos, Proyecto Parejas, Mujer Segura and Mujer Más Segura, STAHR and STAHR-II). Variations in the depth of sampling across the region and collection of risk factor data also likely contributed to the study\'s overall sampling bias. A more comprehensive sample of the infected population in the border region would likely have resulted in more putatively identified transmission links, a higher rate of overall clustering, and a improved understanding of viral migration across the border. Despite this limitation, this study was large and demonstrated linkage of transmission networks across different risk groups and geographically separate populations in the border region. Sampling across risk groups in the Tijuana border region also highlighted the role of such unique geographic areas in bridging transmissions across risk groups, and suggests the need for future research that is attentive to how social, sexual, and drug use networks interact with the built environment. Finally, this analysis highlights the potential usefulness of continuous molecular epidemiologic monitoring of HIV transmission networks, specifically by: 1) providing information about which sexual and PWID networks contribute disproportionately to new infections, and 2) identifying which important socio-demographic or risk groups might be missed in current identification strategies, resulting in improved targeting of prevention efforts.
Author Contributions
Declaration of Interests The following are the supplementary data related to this article.
Introduction Antibodies (Abs) can prevent viral infection through two key mechanisms: neutralizing cell-free virus and targeting virally-infected muscarinic for destruction through either antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) (reviewed in Ackerman and Alter, 2013). While considerable effort has been placed on characterizing broadly neutralizing antibodies (bnAbs) due to their protective capacity in non-human primates, far less is known about ADCC-mediating Abs (reviewed in Ackerman and Alter, 2013; Mascola and Montefiori, 2010; Burke and Barnett, 2007; West et al., 2014). Abs that facilitate ADCC or antibody-dependent cell-mediated viral inhibition (ADCVI) activity, a related metric that quantifies multiple Ab-specific effects on viral replication including ADCC, develop in most infected individuals within the first year following infection and facilitate activity through effector cell mechanisms (Forthal et al., 2001a; Chung et al., 2011a; Alpert et al., 2012; Dugast et al., 2014a). Landmark experiments conducted by Hessell et al. effectively demonstrated a role for antibodies mediating Fc receptor (FcR)-driven effector function by proving that administration of a variant of monoclonal antibody (mAb) b12 that was unable to engage FcRs was 50% less protective against both a high- and low-dose SHIV challenge than mAb b12 with complete effector function, suggesting that both Ab ADCC and neutralizing activity contribute to protection (Hessell et al., 2007, 2009a). Indeed, multiple studies conducted in HIV-infected populations (reviewed in Lewis, 2014), SIV-infected macaques (Banks et al., 2002; Asmal et al., 2011; Sun et al., 2011) and HIV-infected humanized mice (Bournazos et al., 2014) have similarly established a relationship between HIV-specific ADCC or ADCVI antibodies and disease pathogenesis, including reduced viral load (Forthal et al., 2001a; Baum et al., 1996; Ahmad et al., 2001; Nag et al., 2004; Lambotte et al., 2009, 2013; Johansson et al., 2011; Wren et al., 2013), increased CD4 T cell counts (Ahmad et al., 2001, 1994; Chung et al., 2011b) and slower disease progression (Forthal et al., 2001a; Baum et al., 1996; Ahmad et al., 2001; Chung et al., 2011b). These findings suggest that early ADCC responses generated against a new infection may help control virus levels following acquisition. Moreover, Milligan et al. (2015) demonstrated that increased levels of passively acquired HIV-specific ADCC antibody activity in infants correlate with survival, providing evidence for a protective effect of pre-existing antibodies on clinical outcome (Milligan et al., 2015). There is also evidence that ADCC antibodies may impact transmission. Mabuka et al. (2012) correlated higher breast milk IgG ADCC activity that was independent of neutralizing activity with a reduced risk of vertical transmission between mother–infant pairs, providing evidence for a potentially unique role for ADCC in the index case in reducing transmission risk (Mabuka et al., 2012). However, other studies have not detected a significant effect on protection with ADCC-mediating mAbs in either human cohort or macaque model studies (Florese et al., 2006; Dugast et al., 2014b), and it is unclear whether these observations reflect differences in the protective efficacy of the antibodies tested or other methodological factors.