Fetal Cardiac MRI Using Doppler US Gating: Emerging Technology and Clinical Implications.

Fetal cardiac MRI using Doppler US gating is an emerging technique to support prenatal diagnosis of congenital heart disease and other cardiovascular abnormalities. Analogous to postnatal electrocardiographically gated cardiac MRI, this technique enables directly gated MRI of the fetal heart throughout the cardiac cycle, allowing for immediate data reconstruction and review of image quality. This review outlines the technical principles and challenges of cardiac MRI with Doppler US gating, such as loss of gating signal due to fetal movement. A practical workflow of patient preparation for the use of Doppler US-gated fetal cardiac MRI in clinical routine is provided. Currently applied MRI sequences (ie, cine or four-dimensional flow imaging), with special consideration of technical adaptations to the fetal heart, are summarized. The authors provide a literature review on the clinical benefits of Doppler US-gated fetal cardiac MRI for gaining additional diagnostic information on cardiovascular malformations and fetal hemodynamics. Finally, future perspectives of Doppler US-gated fetal cardiac MRI and further technical developments to reduce acquisition times and eliminate sources of artifacts are discussed. Keywords: MR Fetal, Ultrasound Doppler, Cardiac, Heart, Congenital, Obstetrics, Fetus Supplemental material is available for this article. © RSNA, 2024.

Deep learning denoising reconstruction for improved image quality in fetal cardiac cine MRI.

Purpose: This study aims to evaluate deep learning (DL) denoising reconstructions for image quality improvement of Doppler ultrasound (DUS)-gated fetal cardiac MRI in congenital heart disease (CHD). Methods: Twenty-five fetuses with CHD (mean gestational age: 35 ± 1 weeks) underwent fetal cardiac MRI at 3T. Cine imaging was acquired using a balanced steady-state free precession (bSSFP) sequence with Doppler ultrasound gating. Images were reconstructed using both compressed sensing (bSSFP CS) and a pre-trained convolutional neural network trained for DL denoising (bSSFP DL). Images were compared qualitatively based on a 5-point Likert scale (from 1 = non-diagnostic to 5 = excellent) and quantitatively by calculating the apparent signal-to-noise ratio (aSNR) and contrast-to-noise ratio (aCNR). Diagnostic confidence was assessed for the atria, ventricles, foramen ovale, valves, great vessels, aortic arch, and pulmonary veins. Results: Fetal cardiac cine MRI was successful in 23 fetuses (92%), with two studies excluded due to extensive fetal motion. The image quality of bSSFP DL cine reconstructions was rated superior to standard bSSFP CS cine images in terms of contrast [3 (interquartile range: 2-4) vs. 5 (4-5), P < 0.001] and endocardial edge definition [3 (2-4) vs. 4 (4-5), P < 0.001], while the extent of artifacts was found to be comparable [4 (3-4.75) vs. 4 (3-4), P = 0.40]. bSSFP DL images had higher aSNR and aCNR compared with the bSSFP CS images (aSNR: 13.4 ± 6.9 vs. 8.3 ± 3.6, P < 0.001; aCNR: 26.6 ± 15.8 vs. 14.4 ± 6.8, P < 0.001). Diagnostic confidence of the bSSFP DL images was superior for the evaluation of cardiovascular structures (e.g., atria and ventricles: P = 0.003). Conclusion: DL image denoising provides superior quality for DUS-gated fetal cardiac cine imaging of CHD compared to standard CS image reconstruction.

Personalization of thoracoabdominal CT examinations using scanner integrated clinical decision support systems - Impact on the acquisition technique, scan range, and reconstruction type.

OBJECTIVES: This study evaluates the impact of a scanner-integrated, customized clinical decision support system (CDSS) on the acquisition technique, scan range, and reconstruction in thoracoabdominal CT. MATERIALS AND METHODS: We applied CDSS in contrast-enhanced examinations of the trunk with various clinical indications on a recent scanner with the capability of dual-energy CT (DECT), anatomic landmark detection (ALD), and iterative metal-artifact reduction (MAR). Simple and comprehensive questions about the patient's breath hold capability, the anatomical region of interest, and metal implants can be answered after the localizer. The acquisition technique (single energy, SECT, or dual energy), scan range (chest-abdomen-pelvis or chest-abdomen), and reconstruction technique (with or without MAR) were then automatically adapted in the examination protocols in coherence with these selections. Retrospectively, we compared the usage rates for these techniques in 624 examinations on the study scanner with 740 examinations on a comparable scanner without CDSS. Subgroup analysis of effective dose (ED), scan duration, and image quality (IQ) was performed in the study group. RESULTS: CDSS leads to an increased usage rate of DECT (64.4% vs. 2.8%) and MAR (75.4% vs. 44.0%). All scan range adaptations by ALD were successful. The resulting subjective IQ between single energy and DECT acquisitions was comparable (all p > 0.05). Scan duration was significantly longer in DECT than in SECT (16.9 s vs. 6.5 s; p < 0.001). However, the objective IQ was significantly higher in DECT (CNRD 2.1 vs. 1.8; p < 0.01), and the ED significantly lower (6.7 mSv vs. 7.6 mSv; p = 0.004). CONCLUSION: CDSS for thoracoabdominal CT leads to a substantially increased usage rate of innovative techniques during acquisition and reconstruction. Patients with adapted protocols benefit from improved image quality and increased post-processing options at lower radiation doses.

Antigen pressure from two founder viruses induces multiple insertions at a single antibody position to generate broadly neutralizing HIV antibodies.

Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population "arms" that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.

Evaluation of Archival HIV DNA in Brain and Lymphoid Tissues.

HIV reservoirs persist in anatomic compartments despite antiretroviral therapy (ART). Characterizing archival HIV DNA in the central nervous system (CNS) and other tissues is crucial to inform cure strategies. We evaluated paired autopsy brain-frontal cortex (FC), occipital cortex (OCC), and basal ganglia (BG)-and peripheral lymphoid tissues from 63 people with HIV. Participants passed away while virally suppressed on ART at the last visit and without evidence of CNS opportunistic disease. We quantified total HIV DNA in all participants and obtained full-length HIV-envelope (FL HIV-env) sequences from a subset of 14 participants. We detected HIV DNA (gag) in most brain (65.1%) and all lymphoid tissues. Lymphoid tissues had higher HIV DNA levels than the brain (P < 0.01). Levels of HIV gag between BG and FC were similar (P > 0.2), while OCC had the lowest levels (P = 0.01). Females had higher HIV DNA levels in tissues than males (gag, P = 0.03; 2-LTR, P = 0.05), suggesting possible sex-associated mechanisms for HIV reservoir persistence. Most FL HIV-env sequences (n = 143) were intact, while 42 were defective. Clonal sequences were found in 8 out of 14 participants, and 1 participant had clonal defective sequences in the brain and spleen, suggestive of cell migration. From 10 donors with paired brain and lymphoid sequences, we observed evidence of compartmentalized sequences in 2 donors. Our data further the idea that the brain is a site for archival HIV DNA during ART where compartmentalized provirus may occur in a subset of people. Future studies assessing FL HIV-provirus and replication competence are needed to further evaluate the HIV reservoirs in tissues. IMPORTANCE HIV infection of the brain is associated with adverse neuropsychiatric outcomes, despite efficient antiretroviral treatment. HIV may persist in reservoirs in the brain and other tissues, which can seed virus replication if treatment is interrupted, representing a major challenge to cure HIV. We evaluated reservoirs and genetic features in postmortem brain and lymphoid tissues from people with HIV who passed away during suppressed HIV replication. We found a differential distribution of HIV reservoirs across brain regions which was lower than that in lymphoid tissues. We observed that most HIV reservoirs in tissues had intact envelope sequences, suggesting they could potentially generate replicative viruses. We found that women had higher HIV reservoir levels in brain and lymphoid tissues than men, suggesting possible sex-based mechanisms of maintenance of HIV reservoirs in tissues, warranting further investigation. Characterizing the archival HIV DNA in tissues is important to inform future HIV cure strategies.

Fetal Cardiac Cine MRI with Doppler US Gating in Complex Congenital Heart Disease.

Purpose: To apply Doppler US (DUS)-gated fetal cardiac cine MRI in clinical routine and investigate diagnostic performance in complex congenital heart disease (CHD) compared with that of fetal echocardiography. Materials and Methods: In this prospective study (May 2021 to March 2022), women with fetuses with CHD underwent fetal echocardiography and DUS-gated fetal cardiac MRI on the same day. For MRI, balanced steady-state free precession cine images were acquired in the axial and optional sagittal and/or coronal orientations. Overall image quality was assessed on a four-point Likert scale (from 1 = nondiagnostic to 4 = good image quality). The presence of abnormalities in 20 fetal cardiovascular features was independently assessed by using both modalities. The reference standard was postnatal examination results. Differences in sensitivities and specificities were determined by using a random-effects model. Results: The study included 23 participants (mean age, 32 years ± 5 [SD]; mean gestational age, 36 weeks ± 1). Fetal cardiac MRI was completed in all participants. The median overall image quality of DUS-gated cine images was 3 (IQR, 2.5-4). In 21 of 23 participants (91%), underlying CHD was correctly assessed by using fetal cardiac MRI. In one case, the correct diagnosis was made by using MRI only (situs inversus and congenitally corrected transposition of the great arteries). Sensitivities (91.8% [95% CI: 85.7, 95.1] vs 93.6% [95% CI: 88.8, 96.2]; P = .53) and specificities (99.9% [95% CI: 99.2, 100] vs 99.9% [95% CI: 99.5, 100]; P > .99) for the detection of abnormal cardiovascular features were comparable between MRI and echocardiography, respectively. Conclusion: Using DUS-gated fetal cine cardiac MRI resulted in performance comparable with that of using fetal echocardiography for diagnosing complex fetal CHD.Keywords: Pediatrics, MR-Fetal (Fetal MRI), Cardiac, Heart, Congenital, Fetal Imaging, Cardiac MRI, Prenatal, Congenital Heart DiseaseClinical trial registration no. NCT05066399 Supplemental material is available for this article. © RSNA, 2023See also the commentary by Biko and Fogel in this issue.

Nef enhances HIV-1 replication and infectivity independently of SERINC5 in CEM T cells.

A primary function of HIV-1 Nef is the enhancement of viral infectivity and replication. Whether counteraction of the antiretroviral proteins SERINC3 and SERINC5 is the cause of this positive influence on viral growth-rate and infectivity remains unclear. Here, we utilized CRISPR/Cas9 to knockout SERINC3 and SERINC5 in a leukemic CD4-positive T cell line (CEM) that displays nef-related infectivity and growth-rate phenotypes. Viral replication was attenuated in CEM cells infected with HIV-1 lacking Nef (HIV-1ΔNef). This attenuated growth-rate phenotype was observed regardless of whether the coding regions of the serinc3 or serinc5 genes were intact. Moreover, knockout of serinc5 alone or of both serinc5 and serinc3 together failed to restore the infectivity of HIV1ΔNef virions produced from infected CEM cells. Our results corroborate a similar study using another T-lymphoid cell line (MOLT-3) and indicate that the antagonism of SERINC3 and SERINC5 does not fully explain the virology of HIV-1 lacking Nef.

Functional antibodies exhibit light chain coherence.

The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies that bind particular antigens1. In most mammals, antibodies are composed of heavy and light chains that are generated sequentially by recombination of V, D (for heavy chains), J and C gene segments. Each chain contains three complementarity-determining regions (CDR1-CDR3), which contribute to antigen specificity. Certain heavy and light chains are preferred for particular antigens2-22. Here we consider pairs of B cells that share the same heavy chain V gene and CDRH3 amino acid sequence and were isolated from different donors, also known as public clonotypes23,24. We show that for naive antibodies (those not yet adapted to antigens), the probability that they use the same light chain V gene is around 10%, whereas for memory (functional) antibodies, it is around 80%, even if only one cell per clonotype is used. This property of functional antibodies is a phenomenon that we call light chain coherence. We also observe this phenomenon when similar heavy chains recur within a donor. Thus, although naive antibodies seem to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

[Cardiac MRI of congenital heart disease : From fetus to adult]. / Kardiale MRT bei angeborenen Herzfehlern : Vom Fetus zum Erwachsenen.

BACKGROUND: Cardiac magnetic resonance imaging (MRI) is an important diagnostic tool for initial diagnostic workup and follow-up of patients with congenital heart disease (CHD) of different age groups. OBJECTIVES: This review provides an overview of clinically applied MRI sequences for the assessment of CHD, highlights technical developments, and demonstrates key aspects of reporting in specific heart defects. MATERIALS AND METHODS: Presentation of epidemiologic data, summary of studies on MRI sequences and their clinical application, and demonstration of clinical examples. RESULTS: The broad spectrum of congenital heart defects requires the use of various sequences, which can be modified depending on patient age or treatment status. Cine imaging can be used to assess cardiac function and volumes, phase contrast flow measurements allow for the assessment of vessel hemodynamics, and various techniques of MR angiography allow visualization of the thoracic vessels with high spatiotemporal resolution. New developments allow high-resolution vascular imaging without the need for contrast agents, assessment of additional hemodynamic parameters, or fetal cardiac MRI. CONCLUSION: Cardiac MRI can be employed in children as well as in adults with CHD. By using different sequences and considering the treatment status and surgery-related complications, the vast majority of clinical questions can be answered.

Layer-specific Strain Analysis with Cardiac MRI Feature Tracking in Acute Myocarditis.

Purpose: To evaluate the diagnostic performance of layer-specific cardiac MRI feature-tracking (FT) strain analysis in patients with acute myocarditis. Materials and Methods: Seventy patients (mean age, 43 years ± 19 [SD]; 46 men) with clinically defined acute myocarditis and 42 healthy controls who underwent cardiac MRI from March 2014 to November 2018 were retrospectively analyzed. FT-based left ventricular peak systolic global longitudinal strain (GLS) and global circumferential strain (GCS) were assessed at subendocardial, midmyocardial, and subepicardial layers. The 2018 Lake Louise criteria (LLC) were assessed. Patients with myocarditis were dichotomized into two groups: those with preserved and those with reduced ejection fraction. For statistical analysis, unpaired t test, one-way analysis of variance, Pearson correlation, and receiver operating characteristic analysis were used. Results: GLS and GCS values of all layers (eg, midmyocardial GCS: -21.3% ± 5.5 vs -28.0% ± 4.3; P < .001) were impaired in patients with myocarditis compared with controls. Only subepicardial GLS (-20.0% ± 3.3 vs -17.5% ± 3.3; P < .001) and midmyocardial GCS values (-28.0% ± 4.3 vs -23.1% ± 4.3; P < .001) could differentiate between controls and patients with preserved ejection fraction. Midmyocardial GCS correlated with inflammatory myocardial parameters (eg, late gadolinium enhancement percentage, r = 0.48, P < .001). Midmyocardial GCS (area under the receiver operating characteristic curve [AUC], 0.82) and subepicardial GLS (AUC, 0.77) had the highest diagnostic performance for acute myocarditis diagnosis (P < .05 against all other strain parameters). The diagnostic performance of the 2018 LLC was significantly improved by inclusion of these two strain parameters (AUC, 0.92 vs 0.97; P = .04). Conclusion: Diagnostic performance of cardiac MRI FT strain was different between myocardial layers in acute myocarditis, with midmyocardial GCS and subepicardial GLS providing the highest diagnostic performance.Keywords: MRI, Cardiac, Heart, Left Ventricle, Inflammation, Tissue Characterization, MR-Functional Imaging, Feature-Tracking Strain, Acute Myocarditis Supplemental material is available for this article. © RSNA, 2022.

Cardiac MRI in Suspected Acute Myocarditis After COVID-19 mRNA Vaccination.

PURPOSE: To evaluate cardiac MRI characteristics in patients with suspected hypersensitivity myocarditis following mRNA COVID-19 vaccination. MATERIALS AND METHODS: Patients clinically suspected of acute myocarditis after COVID-19 vaccination were retrospectively analyzed and compared against a healthy control group. Cardiac MRI protocol included parameters such as T1 and T2 relaxation times, extracellular volume (ECV), T2 signal intensity ratio, and late gadolinium enhancement (LGE). Lymph node size was assessed in the patient group on the injection side. Student t-test, analyses of variance (ANOVA) with Tukey post-hoc test, and χ2 test were used for statistical analysis. RESULTS: 20 patients with clinically suspected post-vaccine myocarditis (28 ±â€Š12 years; 12 men) and 40 controls (31 ±â€Š11 years; 25 men) were evaluated. According to the 2018 Lake Louise criteria (LLC), patients with clinically suspected myocarditis were further subdivided into an LLC-positive group (n = 9) and an LLC-negative group (n = 11). The mean time of symptom onset after vaccination was 1.1 ±â€Š1.2 days (LLC-positive) and 6.5 ±â€Š9.2 days (LLC-negative). Group differences in inflammatory variables between myocarditis patients and control subjects were more pronounced in the LLC-positive group (e. g., T1 relaxation time: 1041 ±â€Š61 ms [LLC positive] vs. 1008 ±â€Š79 ms [LLC-negative] vs. 970 ±â€Š25 ms [control]; p <.001; or T2 signal intensity ratio 2.0 ±â€Š0.3 vs. 1.6 ±â€Š0.3 [LLC-negative] and vs. 1.6 ±â€Š0.3 [control], p = .012). LLC-positive patients were significantly faster in receiving an MRI after initial symptom onset (8.8 ±â€Š6.1 days vs. 52.7 ±â€Š33.4 days; p = .001) and had higher troponin T levels (3938 ±â€Š5850 ng/l vs. 9 ±â€Š11 ng/l; p <.001). LGE lesions were predominantly located at the subepicardium of the lateral wall. Axillary lymphadenopathy was more frequent in the LLC-positive group compared to the LLC-negative group (8/9 [89 %] vs. 0/11 [0 %], p < 0.001). CONCLUSION: Vaccine-induced myocarditis should be considered in patients with acute symptom onset after mRNA vaccination, especially if elevated serum troponin T is observed. Imaging findings of vaccine-induced myocarditis are similar to virus-induced myocarditis, allowing for the use of the Lake Louise Criteria for diagnostic purposes. KEY POINTS: · Vaccine-induced hypersensitivity myocarditis can be confirmed with cardiac MRI. · Especially patients with sudden onset of symptoms and elevated serum troponin T had positive cardiac MRI findings. · Cardiac MRI characteristics of vaccine-induced myocarditis are similar to those in virus-induced myocarditis. CITATION FORMAT: · Kravchenko D, Isaak A, Mesropyan N et al. Cardiac MRI in Suspected Acute Myocarditis After COVID-19 mRNA Vaccination. Fortschr Röntgenstr 2022; 194: 1003 - 1011.

Author Correction: Vaccine elicitation of HIV broadly neutralizing antibodies from engineered B cells.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20304-y.

Vaccine elicitation of HIV broadly neutralizing antibodies from engineered B cells.

HIV broadly neutralizing antibodies (bnAbs) can suppress viremia and protect against HIV infection. However, their elicitation is made difficult by low frequencies of appropriate precursor B cell receptors and the complex maturation pathways required to generate bnAbs from these precursors. Antibody genes can be engineered into B cells for expression as both a functional antigen receptor on cell surfaces and as secreted antibody. Here, we show that HIV bnAb-engineered primary mouse B cells can be adoptively transferred and vaccinated in immunocompetent mice resulting in the expansion of durable bnAb memory and long-lived plasma cells. Somatic hypermutation after immunization indicates that engineered cells have the capacity to respond to an evolving pathogen. These results encourage further exploration of engineered B cell vaccines as a strategy for durable elicitation of HIV bnAbs to protect against infection and as a contributor to a functional HIV cure.

Inconsistent reversal of HIV-1 latency ex vivo by antigens of HIV-1, CMV, and other infectious agents.

BACKGROUND: A reservoir of replication-competent but latent virus is the main obstacle to a cure for HIV-1 infection. Much of this reservoir resides in memory CD4 T cells. We hypothesized that these cells can be reactivated with antigens from HIV-1 and other common pathogens to reverse latency. RESULTS: We obtained mononuclear cells from the peripheral blood of antiretroviral-treated patients with suppressed viremia. We tested pools of peptides and proteins derived from HIV-1 and from other pathogens including CMV for their ability to reverse latency ex vivo by activation of memory responses. We assessed activation of the CD4 T cells by measuring the up-regulation of cell-surface CD69. We assessed HIV-1 expression using two assays: a real-time PCR assay for virion-associated viral RNA and a droplet digital PCR assay for cell-associated, multiply spliced viral mRNA. Reversal of latency occurred in a minority of cells from some participants, but no single antigen induced HIV-1 expression ex vivo consistently. When reversal of latency was induced by a specific peptide pool or protein, the extent was proportionally greater than that of T cell activation. CONCLUSIONS: In this group of patients in whom antiretroviral therapy was started during chronic infection, the latent reservoir does not appear to consistently reside in CD4 T cells of a predominant antigen-specificity. Peptide-antigens reversed HIV-1 latency ex vivo with modest and variable activity. When latency was reversed by specific peptides or proteins, it was proportionally greater than the extent of T cell activation, suggesting partial enrichment of the latent reservoir in cells of specific antigen-reactivity.

Sensitivity to monoclonal antibody 447-52D and an open env trimer conformation correlate poorly with inhibition of HIV-1 infectivity by SERINC5.

The host protein SERINC5 inhibits the infectivity of HIV-1 virions in an Env-dependent manner and is counteracted by Nef. The conformation of the Env trimer reportedly correlates with sensitivity to SERINC5. Here, we tested the hypothesis that the "open" conformation of the Env trimer revealed by sensitivity to the V3-loop specific antibody 447-52D directly correlates with sensitivity to SERINC5. Of five Envs tested, SF162 was the most sensitive to neutralization by 447-52D, but it was not the most sensitive to SERINC5; instead the Env of LAI was substantially more sensitive to SERINC5 than all the other Envs. Mutational opening of the trimer by substitution of two tyrosines that mediate interaction between the V2 and V3 loops sensitized the Envs of JRFL and LAI to 447-52D as previously reported, but only BaL was sensitized to SERINC5. These data suggest that trimer "openness" is not sufficient for sensitivity to SERINC5.

An MPER antibody neutralizes HIV-1 using germline features shared among donors.

The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. Here we describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. A recombinant sublineage variant pan-neutralizes a 130-isolate panel at 1.4 µg/ml (IC50). Notably, a germline revertant with mature CDR3s neutralizes 12% of viruses and still binds MPER after DJ reversion. Crystal structures of lipid-bound PGZL1 variants and cryo-EM reconstruction of an Env-PGZL1 complex reveal how these antibodies recognize MPER and viral membrane. Discovery of common genetic and structural elements among MPER antibodies from different patients suggests that such antibodies could be elicited using carefully designed immunogens.

Plasma Membrane-Associated Restriction Factors and Their Counteraction by HIV-1 Accessory Proteins.

The plasma membrane is a site of conflict between host defenses and many viruses. One aspect of this conflict is the host's attempt to eliminate infected cells using innate and adaptive cell-mediated immune mechanisms that recognize features of the plasma membrane characteristic of viral infection. Another is the expression of plasma membrane-associated proteins, so-called restriction factors, which inhibit enveloped virions directly. HIV-1 encodes two countermeasures to these host defenses: The membrane-associated accessory proteins Vpu and Nef. In addition to inhibiting cell-mediated immune-surveillance, Vpu and Nef counteract membrane-associated restriction factors. These include BST-2, which traps newly formed virions at the plasma membrane unless counteracted by Vpu, and SERINC5, which decreases the infectivity of virions unless counteracted by Nef. Here we review key features of these two antiviral proteins, and we review Vpu and Nef, which deplete them from the plasma membrane by co-opting specific cellular proteins and pathways of membrane trafficking and protein-degradation. We also discuss other plasma membrane proteins modulated by HIV-1, particularly CD4, which, if not opposed in infected cells by Vpu and Nef, inhibits viral infectivity and increases the sensitivity of the viral envelope glycoprotein to host immunity.