Spotlight Case Part 2: Hypergammaglobulinemia and defective humoral immunity in HIV-infected patients

June 12, 2015

By Stephen Armenti, MD

Peer Reviewed

Please see Part 1 of this Spotlight Case which can be found here.

Case Report

A 45-year-old man with a history of mild intermittent asthma presented with two days of right knee pain and swelling accompanied by subjective fevers, shaking chills, and night sweats. He also reported one day of right calf and left groin pain. The patient denied a history of joint trauma, underlying joint disease, or surgery. There was no history of intravenous drug use, recent travel, or preceding illnesses. He was sexually active with women and reported inconsistent condom use in the past.

On physical examination, the patient was in no distress but was unable to get out of bed due to pain. His heart rate was 107/min and temperature was 101°F. The right knee was erythematous and warm with diffuse swelling and decreased range of motion. He had pitting edema extending from the right foot to the base of the right knee. There was tenderness in the left groin, and movement of the left hip elicited severe pain. Two 4 x 4 centimeter areas of fluctuance were noted over the right medial calf and left sternoclavicular joint. There were no meningeal signs or abnormal findings on pulmonary or cardiac exam.

The white blood cell count was 21,000/mm3 with 86% neutrophils. The erythrocyte sedimentation rate and C-reactive protein were elevated to 126 mm/hr and 261 mg/L, respectively. Labs were otherwise significant for a normocytic anemia (hemoglobin 9.5 g/dL) and serum protein-albumin gap of 5. A polyclonal hypergammaglobulinemia with IgG predominance was noted. A chest radiograph showed bilateral pleural effusions, greater on the right than on the left.

Arthrocentesis of the right knee performed before the initiation of antibiotics revealed purulent synovial fluid with a white blood cell count of 9960/mm3 (88% polymorphonuclear leukocytes). Two sets of joint fluid cultures were positive for Streptococcus pneumoniae. Blood cultures were sterile. Magnetic resonance imaging of the left hip showed a thickened enhancing synovium with surrounding myositis, consistent with a septic joint. Soft tissue abscesses of the right calf and left chest were also noted on imaging. A transthoracic echocardiogram revealed no evidence of vegetations or significant valvular disease. A transesophageal echocardiogram was not performed. The patient was started on intravenous ceftriaxone for disseminated pneumococcal disease. Surgical drainage of the left hip and repeat aspiration of the right knee disclosed significant purulence at both sites, although synovial fluid cultures were negative. On hospital day 3, the patient was found to be HIV positive with a CD4 count of 283 and a viral load of 3070 copies/mL.


Invasive pneumococcal disease can be a life-threatening infection in immunocompromised patients, particularly in developing countries. Not only are HIV-positive patients more frequently colonized with multiple serotypes of Streptococcus pneumoniae, but defects in mucosal immunity brought on by HIV infection allow for invasive disease. Invasive infection remains a significant risk even in patients with a low viral load and a “reconstituted” immune system following adequate treatment with anti-retroviral therapy (ART) [1]. Thus, there appear to be permanent derangements in immune surveillance brought on by HIV infection that predispose to invasive pneumococcal disease. Here, we will explore the correlation between dysregulation of humoral immunity and the mechanism of disseminated pneumococcal infection in HIV-positive patients.

Although loss of T-cell-mediated immunity is the hallmark of HIV infection, initial observations pointed towards similar deficits in humoral immunity. These studies showed that B-cells in HIV-positive patients had reduced antigenic responses to T-cell-independent antigen stimulation [2]. This deficiency was evidenced by the lack of lasting immunity in HIV-positive patients following immunization with pneumococcal vaccines, which require B-cell function. How does HIV affect B-cell responses? Paradoxically, rather than a reduction in immunoglobulin production, it was determined that HIV-positive patients typically display elevated immunoglobulin levels. The key finding in understanding this dichotomy was that the overall number of immunoglobulin-producing B-cells was less important than their identity and fate. During early HIV infection, there are striking shifts in B-cell populations. The majority of B-cells in the peripheral blood of uninfected individuals are either naïve B-cells or memory B-cells. During HIV infection, there are fewer naïve memory B-cells and an increase in plasma and terminally differentiated “exhausted” B-cells [3]. Exhausted B-cells often produce poorly effective anti-HIV antibodies, and have “burned out” due to chronic viral infection and antigen stimulation. These cells fail to appropriately migrate to germinal centers in lymph nodes, have a reduced diversification of globulin production and lead to overproduction of relatively few immunoglobulins. Conversely, memory B-cells, essential for the continued response to encapsulated pathogens such as S. pneumoniae, are specifically diminished. Furthermore, specific subclasses of immunoglobulins appear to be more affected than others. Pneumococcal polysaccharide capsular antigens most often stimulate production of the IgG2 subclass. Although overall levels of IgG-type globulins are elevated in HIV-positive individuals, IgG2 specifically fails to expand following vaccination with pneumococcal vaccines [4]. Thus, chronic HIV viremia is associated with the expansion of ineffective B-cell subpopulations, including hyperactivated and exhausted B cells, which collectively contribute to humoral dysregulation [5].

HIV itself is incapable of infecting B-cells or plasma cells directly. Still, as mentioned above, many effects of humoral dysregulation by HIV appear to occur in a T-cell-independent manner. Given this paradox, what is the molecular mechanism of humoral dysregulation? Recent studies have started to directly interrogate the role of HIV viral antigens in this process. HIV glycoprotein gp120 can bind directly to antigen-presenting dendritic cells, inhibit cytokine secretion, and prevent specific humoral immune responses to invading pathogens by suppressing the secretion of B-cell activation factor of the TNF-family (BAFF) [6, 7]. In contrast, gp120 can also function as a superantigen, resulting in aberrant activation and expansion of B-cells and grossly elevated oligoclonal immunoglobulin levels. Thus, although likely not the sole determinant, molecules like gp120 represent a potential link between the grossly elevated immunoglobulin levels seen in HIV infection together with the concomitant paradoxical immune suppression.

Disseminated pneumococcemia and septic arthritis are well documented, albeit relatively uncommon, presentations in HIV-positive patients. Specific correlations have not been drawn between the relative incidence of gammopathy and risk of pneumococcal infection. Nevertheless, an attractive hypothesis is that the deficits in specific immunoglobulin subtypes provide a predisposition to developing a disseminated infection. Going forward, what are the best therapeutic recommendations given the current evidence and natural history of humoral immune dysfunction in HIV-positive patients? As mentioned above, delayed ART initiation may lead to permanent changes in B-cell distributions. Therefore, rapid initiation of ART may reverse the B-cell population changes that occur early in disease [3]. Vaccination is an essential preventive intervention for S. pneumoniae infection in HIV patients. The 7-valent conjugate vaccine (PCV-7) has been shown to effectively prevent pneumococcal disease in HIV patients [8]. Furthermore, although it has not been directly studied in HIV-positive individuals, PCV-13 is empirically recommended over PCV-7 given the broader serotype coverage. Conjugate vaccines should be administered prior to the polysaccharide vaccine PPSV-23 [9]. This combined “prime-boost” strategy is the currently recommended immunization in HIV patients. However, if not initiated early, the effectiveness of PPSV-23 falls off after CD4 counts drop below 200 cells/mm3. Lastly, patients with CD4 counts below 200 cells/mm3 are advised to take co-trimoxazole prophylaxis, which reduces the rate of pneumonia, diarrhea and malaria. Although this prevention strategy has little effect on the colonization rate of S. pneumonia and, if anything, increases the rate of resistance patterns [10], there is a significant decrease in the rate of bacteremia and pneumonia due to S. pneumoniae [11].

As a final comment, HIV infection presents a well-established risk factor for plasma cell disorders, and therefore follow-up and surveillance for the development of a more worrisome monoclonal gammopathy may be warranted. Regardless of precautions, disseminated pneumococcal infections will remain a risk in this patient population, and consistent monitoring of anti-retroviral efficacy and close follow-up is essential for long-term success.

Dr. Stephen Armenti is a recent graduate of NYU School of Medicine

Peer Reviewed by Howard Leaf, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Jordano Q, Falco V, Almirante B, et al. Invasive pneumococcal disease in patients infected with HIV: still a threat in the era of highly active antiretroviral therapy. Clinical Infectious Diseases 2004:38(11), 1623–1628 (2004).

2. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. NEJM 1983:309, 453–458.

3. Moir S, Buckner CM, Ho J, et al. B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy. Blood 2010:116(25), 5571–5579.

4. Payeras A, Martinez P, Mila J, et al. Risk factors in HIV-1-infected patients developing repetitive bacterial infections: toxicological, clinical, specific antibody class responses, opsonophagocytosis and Fc-gamma RIIa polymorphism characteristics. Clinical and Experimental Immunology 2002:130(2), 271–278.

5. Moir, S. & Fauci, A. S. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. Journal of Allergy and Clinical Immunology 2008:122(1), 223-248.

6. Chung, NPY, Matthews K, Klasse PJ, Sanders RW, Moore JP. HIV-1 gp120 impairs the induction of B cell responses by TLR9-activated plasmacytoid dendritic cells. Journal of Immunololgy 2012:189(11), 5257–5265.

7. Martinelli, E. et al. HIV-1 gp120 inhibits TLR9-mediated activation and IFN-alpha secretion in plasmacytoid dendritic cells. Proceedings of the National Academy of Sciences. 2007:104(9), 3396–3401.

8. French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pnuemococcal conjugate vaccine in HIV-infected adults. New England Journal of Medicine. 2010:362(9), 812-22.

9. Lesprit P, Pedrono G, Molina JM, et al. Immunological efficacy of a prime-boost pneumococcal vaccination in HIV-infected adults. AIDS. 2007:21(18), 2425-34

10. Everett DB, Mukaka M, Denis B, et al. Ten years of surveillance for invasive Streptococcus pneumoniae during the era of antiretroviral scale-up and cotrimazole prophylaxis in Malawi. PloS One. 2011:6(3), e17765.

11. Anglaret X, Chene G, Attia A, et al. Early chemoprophylaxis with trimethoprim-sulfamethoxazole for HIV-1-infected adults in Abidjan, Côte d’lvoire: a randomised trial. Cotrimo-Cl Study Group.