Understanding how antibody responses to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches and vaccination for COVID-19. Here we profile the antibody responses of 162 COVID-19 symptomatic patients in the COVID-BioB cohort followed longitudinally for up to eight months from symptom onset to find SARS-CoV-2 neutralization, as well as antibodies either recognizing SARS-CoV-2 spike antigens and nucleoprotein, or specific for S2 antigen of seasonal beta-coronaviruses and hemagglutinin of the H1N1 flu virus. The presence of neutralizing antibodies within the first weeks from symptoms onset correlates with time to a negative swab result (p = 0.002), while the lack of neutralizing capacity correlates with an increased risk of a fatal outcome (p = 0.008). Neutralizing antibody titers progressively drop after 5–8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities, with IgG to spike antigens providing the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporarily boosted, and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Our results thus suggest compromised immune responses to the SARS-CoV-2 spike to be a major trait of COVID-19 patients with critical conditions, and thereby inform on the planning of COVID-19 patient care and therapy prioritization.

The conserved surfaces of the human immunodeficiency virus (HIV)-1 envelope involved in receptor binding represent potential targets for the development of entry inhibitors and neutralizing antibodies. Using structural information on a CD4-gp120-17b antibody complex, we have designed a 27-amino acid CD4 mimic, CD4M33, that presents optimal interactions with gp120 and binds to viral particles and diverse HIV-1 envelopes with CD4-like affinity. This mini-CD4 inhibits infection of both immortalized and primary cells by HIV-1, including primary patient isolates that are generally resistant to inhibition by soluble CD4. Furthermore, CD4M33 possesses functional properties of CD4, including the ability to unmask conserved neutralization epitopes of gp120 that are cryptic on the unbound glycoprotein. CD4M33 is a prototype of inhibitors of HIV-1 entry and, in complex with envelope proteins, a potential component of vaccine formulations, or a molecular target in phage display technology to develop broad-spectrum neutralizing antibodies.

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␣-defensins are antibiotic peptides that act as natural inhibitors of HIV-1 infection. However, the mechanisms of such inhibition are still unclear. Here we demonstrate that ␣-defensins block the earliest steps in the viral infectious cycle, as documented using an HIV-1 envelopemediated cell-fusion assay. A broad-spectrum inhibitory activity was observed on primary and laboratory-adapted HIV-1 isolates irrespective of their coreceptor specificity and genetic subtype. A primary mechanism of such inhibition was identified as the ability of ␣-defensins to bind specifically both to the primary HIV-1 cellular receptor, CD4, and to the viral envelope glycoprotein, gp120. Moreover, treatment of CD4 ؉ T cells with ␣-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with ␣-defensins were mapped to the D1 domain of CD4 and to a surface contiguous to the CD4-and coreceptorbinding sites of gp120. Consistent with these findings, ␣-defensins inhibited the binding of gp120 to CD4. These data demonstrate that ␣-defensins specifically block the initial phase of the HIV infectious cycle and modulate the expression of CD4, a critical receptor in the physiology of T-cell activation. IntroductionEvidence suggests that a concerted action of innate and adaptive immune responses is essential for the effective containment and, ultimately, the clearance of invading microorganisms. 1 The innate immune system is phylogenetically more archaic and constitutes the first line of antimicrobial defense, characterized by a rapid response time; however, it is limited in its target specificity. By contrast, the adaptive immune system has evolved refined molecular devices for the recognition of a wide variety of specific epitopes, but a lag time is required for its functional activation. Once activated, most of the cells involved in both innate and cognate immune responses secrete soluble factors, including cytokines, chemokines, antibiotic peptides, and others, which can directly antagonize infectious microorganisms and/or contribute to the recruitment and activation of other immune cells, thereby amplifying the cascade of defense mechanisms and bolstering their effectiveness. 2,3 In HIV infection, various host-derived soluble factors with antiviral activity have been described, which act by both specific and nonspecific mechanisms. These include chemokines such as RANTES, MIP-1␣, and MIP-1␤ 4 ; cytokines such as the interferons, IL-10, IL-13, IL-16, transforming growth factor-␤, and others 5 ; as well as, more recently, defensins. [6][7][8][9] Defensins are natural antibiotic peptides that play an important role in innate immune responses by acting as broad-spectrum antibacterial, antifungal, and antiviral effector molecules 10 as well as by enhancing certain adaptive immune responses. 11 ␣-defensins 1 to 3 are 3-to 4-kDa cationic peptides (29 to 30 amino acids [aa]) characterized by a conserved 6-cysteine motif, with 3 disulfide bonds that impose a characteristic ␤-sheet ...

We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. We studied 19 families identified through the analysis of unrelated consecutive patients. The cumulative incidence of the disease was 15% at 60 years, 21% at 70 years, and 32% at 80 years. This study provides accurate estimates of G2019S penetrance by minimizing the selection bias.