Impact of HIV on Immunoglobulin Levels in CVID A primary immune deficiency Defined by hypogammaglobulinemia Males and females equally affected Many clinical manifestations B cell numbers normal or reduced T cell abnormalities common Pathogenesis not well understood HIV is associated with B cell hyperactivity and elevated blood immunoglobulin levels polyclonal and virus-specific B cell activation both nonspecific and specific antibody responses Mechanism of induction of hypergammaglobulinemia not well understood Common Variable Immune Deficiency (CVID) HIV-1 An antigen-bound immunoglobulin molecule Lulu Sun Dr. C.M. Tsoukas

Patients with Concomitant HIV and CVID There have been published reports of four CVID patients who, upon contracting HIV, had a recovery of immunoglobulin production We have an HIV patient (13603) whose hypogammaglobulinemia only manifested itself upon anti- retroviral therapy (ART) suggests HIV was somehow masking the defect that caused low immunoglobulin levels A B Figure 1. Effect of antiretroviral therapy (ART) on viral load and immunoglobulin levels in a patient with concomitant HIV and CVID.

Hypothesis and Methods HIV increases immunoglobulin production in CVID patients, possibly by masking a CVID defect in the BAFF signalling pathway BAFF/BAFFR pathway - B cell survival and homeostasis, isotype switching, Ab responses Serum BAFF is elevated in HIV patients Defects in TACI and BAFF-R in CVID patients TACIBCMA BAFF-R BAFF Hypothesis: Methods: 4 subject groups: HIV/CVID patient, HIV patients (high and low viral load), CVID patients, normal controls Compare: T cell numbers, B cell numbers, subsets within B cell populations (FACS) BAFF serum levels (ELISA) Cell surface molecule expression: BAFF, BAFFR, BCMA, TACI, (FACS) Cellular proliferation in response to antigens, mitogens, and CD3/CD28 (FACS) BAFF downstream signaling components: non-canonical NFkB pathway